An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection

Abstract

It has been known for many years that the angiotensin-converting enzyme 2 (ACE2) is a cell surface enzyme involved in the regulation of blood pressure. More recently, it was proven that the severe acute respiratory syndrome coronavirus (SARS-CoV-2) interacts with ACE2 to enter susceptible human cells. This functional duality of ACE2 tends to explain why this molecule plays such an important role in the clinical manifestations of coronavirus disease 2019 (COVID-19). At the very start of the pandemic, a publication from our Institute (entitled “ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome”), was one of the first reviews linking COVID-19 to the duplicitous nature of ACE2. However, even given that COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin system (RAS), we were still far from understanding the complexity of the mechanisms which are controlled by ACE2 in different cell types. To gain insight into the physiopathology of SARS-CoV-2 infection, it is essential to consider the polymorphism and expression levels of the ACE2 gene (including its alternative isoforms). Over the past 2 years, an impressive amount of new results have come to shed light on the role of ACE2 in the pathophysiology of COVID-19, requiring us to update our analysis. Genetic linkage studies have been reported that highlight a relationship between ACE2 genetic variants and the risk of developing hypertension. Currently, many research efforts are being undertaken to understand the links between ACE2 polymorphism and the severity of COVID-19. In this review, we update the state of knowledge on the polymorphism of ACE2 and its consequences on the susceptibility of individuals to SARS-CoV-2. We also discuss the link between the increase of angiotensin II levels among SARS-CoV-2-infected patients and the development of a cytokine storm associated microvascular injury and obstructive thrombo-inflammatory syndrome, which represent the primary causes of severe forms of COVID-19 and lethality. Finally, we summarize the therapeutic strategies aimed at preventing the severe forms of COVID-19 that target ACE2. Changing paradigms may help improve patients’ therapy.

Introduction

Present in a large number of tissues, including endothelial cells of the arteries, arterioles, and venules of the heart and kidney, angiotensin-converting enzyme 2 (ACE2) is a fascinating molecule which plays a crucial role in maintaining blood pressure homeostasis. ACE2 is only one of the actors in a complex biological network known as the renin-angiotensin system (RAS). ACE2 mainly exerts its functions by regulating the ratio of two major mediators: angiotensin II (Ang II) and angiotensin-[1–7; Ang-(1–7)]. Ang II synthesis is catalyzed by angiotensin-converting enzyme (ACE) while Ang-(1–7) is obtained after hydrolysis of Ang II by ACE2. Ang-(1–7) can also be generated from Ang-(1–9) formed after the action of ACE2 on Ang I by the action of ACE itself. Despite their contrasting physiological functions, the ACE2 is considered to have evolved through ACE gene duplication and exhibits 42% amino acid homology with ACE (Donoghue et al., 2000; Turner and Hooper, 2002; Towler et al., 2004).

Besides being widely studied in cardiology, ACE2 became attractive for other fields of medical sciences and, particularly, virology (Devaux et al., 2020). In 2003 a novel coronavirus infecting humans, the severe acute respiratory syndrome coronavirus (SARS-CoV, provisionally renamed SARS-CoV-1) emerged in Asia, causing an outbreak of severe pneumopathy (Ksiazek et al., 2003; Marra et al., 2003; Rota et al., 2003). ACE2 was demonstrated to be the cellular receptor for SARS-CoV-1, as it had been previously reported for another coronaviruses infecting humans, HCoV-NL63, a coronavirus causing the common winter cold (Hofmann et al., 2005; Li et al., 2007; Ge et al., 2013; Graham et al., 2013). In 2019, new cases of severe pneumopathy were reported in China, with the disease being characterized by a multiple organ dysfunction syndrome (MODS) as well as acute respiratory distress syndrome (ARDS) sometimes requiring the need for ventilation or extracorporeal membrane oxygenation (ECMO). The severe forms of the disease lead to death in ∼ 0.5–2.5% of cases, with a high fatality risk increasing with age and the existence of underlying comorbidities (Huang et al., 2020; Zhou et al., 2020; Zhu et al., 2020). Under chest computerized tomography (CT) scans, the majority of patients show bilateral ground glass-like opacities and subsegmental areas of consolidation indicative of pneumonia. This disease was later defined as COVID-19, the aetiological agent of which was found to be a new human coronavirus named severe acute respiratory syndrome coronavirus (SARS-CoV-2). Although not highly symptomatic for the majority of those infected, the virus has spread worlwide causing more than 6 million deaths for ∼603 million reported cases of infections (World Health Organization COVID-19 Dashboard on 6 September 2022; https://covid19.who.int/). SARS-CoV-2 shares 79.5% nucleotide identity with SARS-CoV-1, and both these Sarbecoviruses isolated from humans are genetically close to coronaviruses circulating in wildlife (Ge et al., 2013; Afelt et al., 2018; Wang et al., 2020; Zhou et al., 2020; Frutos et al., 2021). Once SARS-CoV-2 was characterized, the search for its cellular receptor became a priority. Due to the sequence similarity between SARS-CoV-1 and SARS-CoV-2, studies quickly focused on ACE2 and the role of this molecule as a viral entry receptor was demonstrated (Qiu et al., 2020; Yan et al., 2020).

Due to the central role played by ACE2 in maintaining blood pressure homeostasis, the objective of this work is to review the state of knowledge regarding the possible imbalance of the RAS in the context of a SARS-CoV-2 infection and to highlight the role of ACE2 in SARS-CoV-2 infection and replication, as well as its contribution in the severity of COVID-19.

The renin-angiotensin system: A molecular network which regulates blood pressure homeostasis and ion-fluid balance

In humans and other mammals, intravascular RAS plays a key role in maintaining blood pressure homeostasis as well as fluid and salt balance, while tissue RAS is mainly involved in the pathogenesis of inflammatory diseases (Paul et al., 2006; Greenberg, 2008; de Kloet et al., 2010). The kidneys, as a sensor of ion fluid balance and producer of renin, play a fundamental role in the long-term control of arterial pressure (Tigerstedt and Bergman, 1898; Phillips and Schmidt-Ott, 1999; Yim and Yoo, 2008; Prieto et al., 2011; Gonzalez et al., 2017). Active renin is secreted into the blood circulation in response to hypotension or hypernatremia. Upon activation of the juxtaglomerular apparatus of the kidneys’ afferent arterioles, proteases (proconvertase 1, cathepsin B) catalyze the removal of the 20-amino-acid terminal prosegment of prorenin to produce a polypeptide composed of 297 amino-acids (Davis and Freeman, 1976; Hadman et al., 1984; Cohen-Haguenauer et al., 1989; Sealey and Rubattu, 1989; Neves et al., 1996; Muller et al., 1999). The active form of renin cleaves the alpha-globulin angiotensinogen (formerly angiotonin, a 118-amino-acid-long polypeptide), giving rise to angiotensin I (Ang I), the N-terminal decapeptide of angiotensinogen (Goldblatt et al., 1934; Page and Helmer, 1940; James and Sielecki, 1985). The conversion of Ang I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) to the octapeptide Ang II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), requires the cleavage of its C-terminal dipeptide catalyzed by ACE (provisionally named ACE1) expressed at the endothelial surface of the blood vessels, epithelium of the lungs and upper respiratory system (Skeggs et al., 1956; Crisan and Carr, 2000; Wakahara et al., 2007). The vasoconstrictor octapeptide Ang II was evidenced to be a substrate for ACE2, which acts as an essential factor in the RAS pathway homeostasis. By removing a single residue phenylalanine (Phe) from Ang II, the membrane form of ACE2 (mACE2) plays a central role in the synthesis of the cardiovascular protective heptapeptide Ang-(1–7) that acts by limiting the adverse vasoconstrictor and profibrotic effects of Ang II and reduces the oxidative stress of Ang II on endothelial arteries (Crackower et al., 2002; Pena Silva et al., 2012). ACE2 can also catalyze the conversion of Ang I to Ang-(1–9) by removing the C-terminal leucine (Leu) residue of Ang I, but with a catalytic efficiency ∼ 400-fold lower than the hydrolysis of Ang II to produce Ang-(1–7). Besides Ang II and Ang I, ACE2 can cleave several other substrates including des-Arg9-bradykinin (DABK), apelin-13, and dynorphin A-(1–13; Skidgel and Erdos, 1987; Ferrario et al., 1997; Vickers et al., 2002; Oudit et al., 2003) In addition to its membrane form, ACE2 can be found in a soluble form (sACE2) and increasing sACE2 has been reported in patients with cardiomyopathies and heart failure (Epelman et al., 2008). In patients with aortic stenosis, increasing levels of sACE2 associated with reduced myocardial ACE2 gene expression and severe myocardial fibrosis is considered as a death risk biomaker (Rajagopal et al., 2010). Thus, increased sACE2 plasma levels have been associated with heart failure, cardiovascular disease, and cardiac remodeling (Epelman et al., 2009; Sama et al., 2020; Garcia-Escobar et al., 2021). Using animal models, it was shown that knocking out (KO) of the ACE2 gene results in increased levels of Ang II, followed by vasoconstriction reducing coronary blood flow and leading to cardiac dysfunction (Danilczyk et al., 2003). The expression of mACE2 in the kidneys and heart is influenced by salt rich and/or glucose-rich diets, and can be correlated with pathological disorders (Reich et al., 2008; Lavrentyev and Malik, 2009; Bernardi et al., 2012; Wysocki et al., 2013). In the respiratory tract, DABK is a substrate of mACE2 and a decrease in ACE2 could lead to an increase in vascular permeability and fluid extravasation (Chung et al., 2020). Using a mouse animal model, it was found that loss of ACE2 led to activation of the DABK/braddykinin receptor B1 (BKB1R) axis associated with release of proinflammatory chemokines (e.g., CXCL5, MIP2, and TNFα) and increase in neutrophil infiltration (Sodhi et al., 2017).

Resulting from the cleavage of Ang II by the mACE2 protease, Ang-(1–7) exhibits vasodilatory, anti-proliferative, anti-inflammatory, and antifibrotic effects via the G protein-coupled receptor (GPGR) known as Mas 1 (Santos et al., 2003, 2018; Simoes e Silva et al., 2013; Patel et al., 2016; Karnik et al., 2017; Bader et al., 2018). However, biochemical studies have failed to demonstrate a direct interaction between Ang-(1–7) and Mas1 (Gaidarov et al., 2018). In addition to mACE2, several peptidases, including vascular endothelium prolyl peptidases, neprilysin (NEP), and smooth muscle thimet oligopeptidase, can produce Ang-(1–7; Chappell, 2019). NEP and thimet oligopeptides produce Ang-(1–7) directly from Ang I. Ang-(1–7) has been shown to potentiate bradykinin (BK 1–9), a potent vasodilator of the kinin system which mediates its effects through the B2 receptor (BKB2R) abundant in vascular tissue (Jackman et al., 2002). ACE2 overexpression and Ang-(1–7) infusion have beneficial effects on atherosclerosis, whereas ACE2 deficiency accentuates vascular atherosclerosis in animal models (Dong et al., 2008; Thomas et al., 2010; Yang et al., 2013). The up-regulation of the ACE2/Ang-(1–7)/MasR axis promotes the expression of E-cadherin (E-cad) adhesion molecules by suppressing the PAK1/NF-κB/Snail1 pathway (Yu et al., 2016). Moreover, Ang-(1–7) can exert cerebroprotective functions in endothelin-1-induced ischaemic stroke (Mecca et al., 2011).

For many years, it has been known that there is cross-talk between insulin and the RAS, providing possible links between hypertension, obesity, and diabetes (Alderman et al., 1991; Frederich et al., 1992; Velloso et al., 1996; Boustany et al., 2004; Schmieder et al., 2007). Moreover, a low expression of ACE2 mRNA or protein is associated with an increase in AngII levels, hypertension, diabetes and heart disease (Crackower et al., 2002; Diez-Freire et al., 2006; Tikellis et al., 2012; Velkoska et al., 2016).Interestingly, these diseases are the major comorbidities in the severe forms of COVID-19 (Bavishi et al., 2020). The occurrence of specific comorbidities associated with an RAS imbalance could be decisive for the clinical outcome of COVID-19 (Devaux et al., 2020; Rysz et al., 2021).

RAS imbalance and overproduction of harmful Ang II

Clinical investigations have provided convincing evidence that RAS imbalance is capable of stimulating atherosclerosis, which ultimately lead to the rupture of atherosclerosis plaques and thrombosis (Schmidt-Ott et al., 2000; Jacoby and Rader, 2003; Verdecchia et al., 2008). Ang II is the main harmful effector molecule synthesized in excess in situations of RAS imbalance. Ang II, inactivates the vasodilator bradykinin and can control the ion-fluid balance by acting on the adrenal cortex to stimulate the release of aldosterone, leading to sodium and water retention (Jaspard et al., 1993; Brewster and Perazella, 2004; Xue et al., 2012; Aroor et al., 2016; Nishimura, 2017). The action of Ang II (proximal tubule) and aldosterone (collecting duct) are complementary to influence sodium reabsorption across the nephron (Gurley et al., 2011). Thereby, Ang II functions as a powerful regulator of vascular tone and intravascular volume. Increased circulating levels of Ang II is associated with vasoconstriction and hypertension and accelerates thrombosis in arterioles by activating the coagulation cascade and the platelet-derived growth factor (PDGF; Gustafsson and Holstein-Rathlou, 1999; Heeneman et al., 2000; Senchenkova et al., 2010, 2014; Singh and Karnik, 2016; Samavati and Uhal, 2020). It also induces hypertrophy of vascular smooth muscle cells (Berk et al., 1989; Griendling et al., 1997; Funakoshi et al., 2002). Ang II can also exert tissue-specific actions, such as neurotransmission inducing adipocytes growth in adipose tissues (Li and Ferguson, 1993; Massiéra et al., 2001).

These multiple effects of Ang II are obtained through its ability to bind to Ang II type I and type II receptors (AT1R and AT2R, respectively) expressed in arterioles and several organs including the kidney, pancreas, heart, and the brain. The AT1R, a 359-amino-acids protein spanning cell membrane, and AT2R have a 34% nucleic acid sequence homology (Arendse et al., 2019). Ang II can bind to both to AT1R and AT2R, which are receptors with opposite effects (i.e., AT1R mediates vasoconstriction, inflammation and fibrosis while AT2R mediates opposite effects). AT2R is poorly expressed compared to AT1R, which causes the Ang II to primarily exhibit an effect through AT1R (Murphy et al., 1991; de Gasparo et al., 2000; Forrester et al., 2018; Furuhashi et al., 2020). The activation of AT1R by Ang II is transient and associated with the phosphorylation of the receptor by kinases, including PKC and GRKs. The phosphorylated AT1R is internalized through a mechanism that involves β-arrestin 2, the adaptor protein complex 2 (APC2), clathrin, and intersectin 2 (AbdAlla et al., 2000; de Gasparo et al., 2000; Gáborik et al., 2001). These AT1R-mediated signals lead to overexpression of the prorenin receptor (PRR), thereby increasing renin activity and contributing to the local accumulation of Ang II, fibrosis, and hypertension (Nguyen et al., 2002; Advani et al., 2009; Peng et al., 2013; Wang et al., 2014; Xu et al., 2016; Ichihara and Yatabe, 2019). At the opposite, Ang II also exerts a negative feedback signaling on juxtaglomerular cells that reduces the REN gene transcription and renal renin secretion (Naftilan and Oparil, 1978).

The interaction of Ang II with AT1R functions as a pluripotent mediator to enhance oxidative injury by reactive oxygen species (ROS), and endothelial injury by inhibiting nitric oxide (NO) synthesis. Ang II is a potent activator of NADPH oxidase and an inducer of ROS (Garrido and Griendling, 2009). Interestingly, CHOP−/− mice are protected from Ang II-induced NADPH oxidase activation, hypertension, and cardiovascular disease (Kassan et al., 2016). This is consistent with the observation that Ang II increases the transcription of the CHOP and ATF4 genes (Kassan et al., 2012; Spitler and Webb, 2014; Takayanagi et al., 2015). Activation of AT1R by Ang II also induces various signaling pathways, including G-protein-coupled receptors, PKC, serine/threonine kinase, serine tyrosine kinases, ERK/JNK activation, leading to proinflammatory responses characterized by the synthesis of IL-6, TNFα, and other cytokines (Sadoshima et al., 1995; Han et al., 1999; Nataraj et al., 1999; Ruiz-Ortega et al., 2001; Watanabe et al., 2005; Luther et al., 2006; Rushworth et al., 2008; Dikalov and Nazarewicz, 2013). Furthermore, Ang II activates the flow of neutrophils and macrophages to the affected tissues and inhibits the production of NO, leading to vascular injury (Nabah et al., 2004).

ACE2 tissue distribution in human

Angiotensin-converting enzyme 2 is expressed in virtually all organs with higher levels in capillary rich organs such as the lungs, heart, or kidneys (Donoghue et al., 2000; Tipnis et al., 2000; Ferrario and Varagic, 2010; Tikellis and Thomas, 2012; Figure 1). A study of ACE2 mRNA and protein in more than 150 cell types concluded that ACE2 is mainly observed in enterocytes, renal tubules, the gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eyes, and the vasculature. In the respiratory system, its expression was limited to a subset of cells (Hikmet et al., 2020).

Figure 1

Remarkably, in the upper airway, goblet and ciliated cells show the highest expression of ACE2 and are thought to play a major role in human infection with SARS-CoV-2. The expression of the mACE2 protein is highest within regions of the sinonasal cavity and pulmonary alveoli and in the lung parenchyma (Descamps et al., 2020; Ortiz et al., 2020). In normal human lungs, the mACE2 protein is found on a very small subset of alveolar type II epithelial lung cells (Ortiz et al., 2020; Delorey et al., 2021). Alveolar epithelial type II cells (which represent ∼5% of the alveoli and serves at stem cells to generate type I alveolar epithelial cells), are thought to be a main target for SARS-CoV-2 in the respiratory tract and, consequently, can be destroyed during viral replication (Barkauskas et al., 2013). However, ACE2-positive cells are more abundant in the nasal mucosa than in the bronchus (Hikmet et al., 2020). Moreover, the mACE2 peptidase is also expressed in the arterial and venous endothelial cells present in abundance in the lungs and arterial smooth muscles (Hamming et al., 2004). Expression of ACE2 was found to be drastically increased in airway epithelial cells 24 h after SARS-CoV-1 infection (Li et al., 2020). In COVID-19 related ARDS, ACE2 was found to be upregulated in endothelial cells, but not in type II alveolar epithelial lung cells (Gerard et al., 2021).

The expression of ACE2 in the heart is higher than in the lungs and ACE2 is found in the endothelial cells of coronary arteries, arterioles, venules, and capillaries (Danilczyk et al., 2003; Robinson et al., 2020). The mACE2 is strongly expressed in cardiomyocytes, endothelial cells, cardiac fibroblasts, vascular smooth muscle cells, and was also found in cardiac pericytes, which play crucial role in the microvasculature and may be the target for SARS-CoV-2 (Chen et al., 2020; Hikmet et al., 2020). Patients with heart failure show a significant increase in ACE2 mRNA expression (Goulter et al., 2004), suggesting that ACE2 gene overexpression may explain why heart dysfunction is found within the list of COVID-19 comorbidities. In a rat model of diabetic cardiomyopathy, the overexpression of ACE2 attenuates cardiac hypertrophy, myocardial fibrosis, and dysfunction induced by diabetes (Dong et al., 2012). Post-mortem examinations of endomyocardial biopsies from COVID-19 patients highlighted the presence of SARS-CoV-2 in the myocardium (Lindner et al., 2020; Marchiano et al., 2021).

In the kidneys, ACE2 is expressed in the proximal tubule cells, epithelial cells of the Bowman’s capsule, endothelial cells, mesengial cells (glomerulus central area), glomerular podocytes, proximal cell brush border, and cells from the collecting ducts (Aragao et al., 2011; Hikmet et al., 2020; Martinez-Rojas et al., 2020). Patients with diabetic or hypertensive nephropathy had lower glomerular ACE2 expression compared to healthy controls (Mizuiri et al., 2008; Wysocki et al., 2013). Between 3 and 10% of COVID-19 patients have abnormal renal function (diagnosed with elevated creatinine or urea nitrogen), and 7% experienced acute renal injury (Fan et al., 2021). In the pancreas, ACE2 plays a major glycemia-protective role (Pedersen et al., 2013). In testis, the Sertoli cells, which protect germ cells by forming blood-testis barrier, have a high expression of mACE2, suggesting that SARS-CoV-2 might cause reproductive disorders in infected patients (Shen et al., 2020; Fan et al., 2021).

A high expression of ACE2 was reported in the epithelial cells of the oral mucosa. This is rarely seen in esophageal mucosa (mainly composed of squamous epithelial cells) and is abundantly expressed in the glandular cells of the gastric, duodenal, and rectal epithelia, possibly contributing to the oral transmission of SARS-CoV-2 and then to viral spreading into the gastrointestinal tract, a major target for the virus (Lamers et al., 2020; Xu et al., 2020; Devaux et al., 2021a; Osman et al., 2022). mACE2 is highly expressed thorough the ileum where it may cleave circulating Ang II in the mesenteric arterial blood into Ang-(1–7), which is destined for portal circulation and the liver. The mACE2 also exerts RAS-independent functions in the gastrointestinal tract through cleaving carboxy-terminal amino acids from nutrient proteins and by acting as a chaperon for the expression of the B⁰AT1 amino acid transporter (Crackower et al., 2002; Camargo et al., 2009; Singer and Camargo, 2011; Fairweather et al., 2012; Hashimoto et al., 2012; Vuille-Dit-Bille et al., 2015; Wang et al., 2015). The mACE2 regulates the gut homeostasis, microbiota composition, the expression of antimicrobial peptides (Reg3γ, α-defensin, such as HD5 and HD6, β-defensin, and lysozyme; Singer et al., 2012; Perlot and Penninger, 2013; Ferrand et al., 2019). This probably explains the diarrhea that is sometimes observed in SARSCoV-2 patients, and supports the use of antibiotic treatment in COVID-19 patients. In addition, it was reported that HD5 secreted by intestinal Paneth cells, interacts with ACE2 (Wang et al., 2020), suggesting that the presence of HD5 in abundance in the ileal fluid may compete with SARS-CoV-2 to bind to ACE2. The infection of Caco2 cells by SARS-CoV-2 was found to be significantly reduced when cultured in the presence of HD5 and this effect was confirmed on intestinal and lung epithelial cells and for different SARS-CoV-2 variants (Wang et al., 2020; Xu et al., 2021). Although the ACE2 regulation of gut homeostasis was considered to be RAS-independent, α-defensins expression has also been associated with atherosclerosis, being involved in the lipoprotein metabolism in the vessel wall and inhibiting fibrinolysis (Kougias et al., 2005; Nassar et al., 2007; Abdeen et al., 2021).

Structure of the human ACE2 protein

The ACE2 gene encodes a type I transmembrane glycoprotein of ∼ 100 kDa composed of 805 amino acids(Figure 2; Marian, 2013; Gheblawi et al., 2020), including six amino acids (Asn₅₃, Asn₉₀, Asn₁₀₃, Asn₃₂₂, Asn₄₃₂, and Asn₅₄₆), which can potentially be N-glycosylated (Lubbe et al., 2020). This metalloprotease resembles a chimera molecule composed of a single ACE-like catalytic ectodomain (41.8% sequence homology with the amino domain of ACE) fused to a collectrin-like domain (48% homology with collectrin; Donoghue et al., 2000; Zhang et al., 2001). The functional domains of ACE2 include: (i) a N-terminal signal peptide region of 17 amino acid residues; (ii) a peptidase domain (PD; amino acids 19–615) with its zinc binding metalloprotease motif (catalytic domain; amino acids 374–378); (iii) a C-terminal collectrin-like domain (CLD; amino acids 616–768 acting as a regulator of renal amino acid transport and insulin exocytosis), containing a ferredoxin-like fold “neck” domain (amino acids 615–726); and (iv) an hydrophobic transmembrane hydrophobic helix region of 22 amino acids followed by an intracellular cytoplasmic tail of 43 amino acids (Donoghue et al., 2000; Zhang et al., 2001; Cerdà-Costa and Gomis-Rüth, 2014). The C-terminal segment of mACE2 contains a PDZ-binding motif (amino acids 803–805) Thr₈₀₃-Ser₈₀₄-Phe₈₀₅ (TSF_COOH) targeting protein-interacting domains from proteins (SNX27, SHANK3, MAST2, and NHERF2) involved in protein trafficking (Caillet-Saguy and Wolf, 2021; Kliche et al., 2021).

Figure 2

The mACE2 functions predominantly as a monocarboxypeptidase, with a substrate preference for hydrolysis between a proline and a hydrophobic or basic C-terminal residue (Turner and Hooper, 2002). The catalytic domain of mACE2 consists of two subdomains (subdomains 1 and 2) forming the two sides of a long deep cleft bridged together by a hinge region. Upon substrate binding, the two catalytic subdomains undergo a hinge-bending movement and form a binding cavity required to initiate substrate hydrolysis (Towler et al., 2004). The His-Glu-X-X-His motif (or HEXXH motif where X is any amino acid), coordinates a catalytic zinc ion, characteristic of zinc-dependent metalloproteases. The zinc is co-ordinated by His₃₇₄, His₃₇₈, Glu₄₀₂, and one water molecule in the subdomain 1, whereas a chloride ion is co-ordinated by Arg₁₆₉, Trp₄₇₇, and Lys₄₈₁ in the subdomain 2. The Arg₅₁₄ of mACE2 is considered as a residue critical for substrate selectivity (Luther et al., 2006).

Both the PD and neck domains of mACE2 contribute to dimerization, whereas each B⁰AT1 interacts with the neck and TM helix in the adjacent mACE2 (Yan et al., 2020). Complexes of mACE2/B⁰AT1 heterodimers have been evidenced at the intestinal apical membrane but did not occur in lung pneumocytes. Steric hindrance to the B⁰AT1 binding site on mACE2 or down-regulation of mACE2 due to the presence of SARS-CoV-2 is likely to display impaired intestinal tryptophan uptake (Devaux et al., 2021a).

Finally, the Arg₆₅₂ of ACE2 is a target for the catalytic site of proteases ADAM17 and TMPRSS2, which leads to the shedding of a soluble form of ACE2 (sACE2; Heurich et al., 2014; Lanjanian et al., 2021).

The human ACE2 gene variant mRNAs

The prototype human ACE2 cDNA (or ACHE for angiotensin-converting enzyme homolog) was cloned more than 2 decades ago from a human cardiac left ventricle cDNA library and a lymphoma cDNA library (Donoghue et al., 2000; Ferrario and Varagic, 2010). The ACE2 gene, which contains 20 introns and 19 exons maps to chromosome Xp22 and spans 39.98 kb of genomic DNA (Turner and Hooper, 2002). Two isoforms of ACE2 with 18 or 19 exons (v1 and v2) that encode the same protein (805 amino acids) have been described, as well as three other smaller variants: x1–x3 (Chen et al., 2020; Khayat et al., 2020). ACE2 shows similarities with the ACE gene located at chromosome 17q23 (Hubert et al., 1991). Although ACE2 is one of the genes escaping X chromosome inactivation, there is evidence of sex bias (Tukiainen et al., 2017; Cai, 2020; Gay et al., 2021). Indeed, there is a plausible mechanism of androgen-induced expression of ACE2 that contributes to increased susceptibility or severity of COVID-19 in males (Baratchian et al., 2021). The tissue levels of mACE2 represent equilibrium between transcription/translation of mACE2 and shedding rate of sACE2. It was reported that a positive relationship exists between renin and sACE2 levels in male and female subjects, and between sACE2 levels and body mass index (BMI) in males, with possible implication for COVID-19 (Jehpsson et al., 2021). Variations in mACE2 with age were first demonstrated using animal models (Xie et al., 2006). A negative association between age and sACE2 plasma concentrations in people above the age of 55 year-old, was reported (AlGhatrif et al., 2021). The mACE2 deficiency is considered to be linked to cardiovascular disease and diabetes, suggesting that mACE2 deficiency may increase the risk of developing severe COVID-19 (Oudit and Pfeffer, 2020; Verdecchia et al., 2020; Wang et al., 2020).

The transcription of full-length ACE2 (2,721 bp mRNA) is initiated from either a proximal or a distal promoter with tissue-specific differences in their usage (Itoyama et al., 2005; Fan et al., 2021). The proximal site contains a TATA box motif at position-110/−96 of the transcription start site and a GATA motif and two HNF1 binding sites at position-165/−131. The distal site contains YY1/COUP, C/EBPβ, and STAT/FOXA motifs. Site-directed mutagenesis of the human ACE2 promoter region from position −2069 to +20, has enabled the identification of an activating domain in the −516 to −481 region (Kuan et al., 2011) and a potential binding site, ATTTGGA, homologous to that of an Ikaros-like binding domain which can be regulated by the levels of Ang II. It has also been reported that the NAD + -dependent deacetylase silent information regulator T1 (SIRT1 known for its ability to deacetylate proteins such as p53 and forkhead box O), binds to the ACE2 promoter and regulates ACE2 gene expression under condition of energy stress which increase AMP-activated protein kinase, while IL-1β treatment decreased the binding of SIRT1 to the ACE2 promoter (Clarke et al., 2014). In addition, there is a cAMP-responsive element (CREB)-binding site within an upstream region of the start site containing both p300 (a CREB co-activator that relaxes the chromatin and recruits RNA polymerase II) and the CREB site (Figure 3).

Figure 3

The in silico study of candidate binding sites within the 400 bp upstream of the transcription start site identified putative sites for various DNA-binding molecules, with different tissue expression such as CDX2 in the lungs, colon, and terminal ileum; HNF1A in the colon, kidneys, and terminal ileum; FOXA1 in the cervix, colon and terminal ileum; SOX11 in the kidneys, and TCF7/LEF1 in the lungs (Barker and Parkkila, 2020). The ACE2 promoter also contains an androgen receptor (AR) binding site, and AR antagonists (e.g., enzalutamide, apalutamide) have been reported as being able to decrease SARS-CoV-2 infection (Qiao et al., 2021). Moreover, forkhead box A1 (FOXA1; also known as HNF3α) involved in AR signaling, and bromodomain-containing protein 4 (BRD4) binding sites, overlap with open chromatin regions. Bromodomain and extra terminal domain (BET) antagonists (e.g., JQ1, OTX015), inhibit BRD4, a factor able to interact with positive elongation factor (P-TEFb) cyclin-dependent kinase required for transcription elongation through RNA polymerase II (RNA pol II), also decrease SARS-CoV-2 infection through the inhibition of BRD4. The distal-less homeobox 2 (DLX2) and CCAAT/enhancer binding protein epsilon (CEBPE) are more represented in ACE2-expressing cells (Sherman and Emmer, 2021). Evidence for additional transcription factor binding sites (e.g., SP1, CEBP, GATA3, HNF4A, USF1, etc.) has also been reported (Beacon et al., 2021).

Putative binding sites for signal transducer and activator of transcription, STATs (−662 to −647 region and −911 to −897 region), and interferon-regulatory factors, IRFs, have also been demonstrated (Ziegler et al., 2020). Indeed, interferon modulates ACE2 expression and can lead to the transcription of a truncated form of ACE2, designated as deltaACE2 (dACE2) which lacks 356 amino-terminal amino acids and fails to bind to SARS-CoV-2 (Onabajo et al., 2020). The transcription of such a truncated form of ACE2 involves the activation of a promoter located downstream of the transcription start site with a splicing event introducing a new ATG start codon. The analysis of this region identified ISGF-3-, AP-1-, and NF-κB-binding sites (Blume et al., 2021). Treating cells with IFNβ significantly induces the dominant expression of dACE2 over ACE2 (Onabajo et al., 2020). In addition, the possible role of alternatively spliced isoforms of ACE2 in SARS-CoV-2 homing, infectivity, and influence on COVID-19 evolution, should be investigated (Heyman et al., 2021; Nikiforuk et al., 2021). Polymorphisms in ACE2 gene 5′ upstream regions might influence ACE2 expression. Differences greater than 1% of minor allele frequency (MAF) in the 10 Kb region upstream to ACE2 analyzed using data from the 1,000 Genomes project, found 57 polymorphisms (Lanjanian et al., 2021). A single nucleotide polymorphism (SNP), rs5934250, with a change from G to T at approximately 5,700 bp upstream of the start codon of the ACE2 gene, presented a penetration difference among populations. This allele is almost absent in the East Asian population, while it has a MAF in almost half of Europeans (East Asians: 1%; Africans: 10%; South Asians: 22%; Americans: 29%; and Europeans: 47%). Another SNP, rs2097723, also shows a very heterogeneous distribution among populations (Africans: 7%; South Asians: 22%; Europeans: 28%; Americans: 32%; and East Asians: 42%).

Human ACE2 polymorphism

Exploration of the ACE2 genetic polymorphism was conducted to define SNPs associated with hypertension and heart diseases. Special attention was drawn to 14 SNP (rs2285666, rs1978124, rs2074192, rs2106809, rs4830542, rs4240157, rs879922, rs2158083, rs233574, rs1514282, rs1514283, rs4646155, rs4646176, and rs4646188). The best characterized SNP is a splice region variant (rs2285666, G > A, Intron 3/4), known to be associated with hypertension, coronary heart disease, and diabetes (Yang et al., 2015; Pinheiro et al., 2019; Bosso et al., 2020). A number of SNPs, including genotypes of rs2048683, rs233575, rs2158083, rs2074192, rs2106809, rs4240157, rs4646155, and rs4830542 were linked with moderate risks of hypertension, while rs4646188 and rs879922 were linked to high hypertension risks (Yi et al., 2006; Fan et al., 2009; Patnaik et al., 2014; Dai et al., 2015; Meng et al., 2015; Chen et al., 2016; Liu et al., 2018; Luo et al., 2019), and the rs2074192 and rs2106809 were associated with left ventricular hypertrophy in hypertensive patients (Fan et al., 2019). The ACE2 A₁₀₇₅G allele found in China was associated with hypertension and the ACE2 G₈₇₉₀A allele is associated with susceptibility to hypertension, type 2 diabetes, and increased plasma concentration of sACE2 (Niu et al., 2007; Wu et al., 2017; Pinheiro et al., 2019). An allele frequency heterogeneity for the rs2285666 (East Asians: 17%; South Asians: 23%; Americans: 37%; Africans: 48%; Europeans 48%; and with the highest frequency in Indians: 71%) has been reported (Khayat et al., 2020) while the rs4646140 has a MAF ranging from zero in Indians to 13% in Africans. Polymorphisms, including rs233574, rs2074192, and rs4646188 with MAF of 16, 36, and 6%, respectively, were able to induce a significant RNA secondary structure change (Pouladi and Abdolahi, 2021). These alterations may lead to dysregulations in ACE2 transcription/translation or its protein stability. Indeed, in the case of the mutated alleles, the splicing regulatory molecule ETR-3 is unable to bind to the pre-mRNA. Similarly, in the case of the mutated forms of rs2158083 and rs2285666, the binding of YB-1 and hnRNP DL, respectively, are impaired, resulting in exon retention. In the case of the mutated form of rs1514283, the SF2/ASF, and SRp40 proteins bind and lead to the creation of a new intron splicing enhancer and exon inclusion. In the case of the mutated form of rs879922, there is a possibility of interaction with the SC35 and DAZAP1 proteins that leads to exon inclusion. In addition, the binding of proteins of the hnRNP A1, A0, A2/B1, D, and DL family creates a new intronic splice silencer and intron exclusion. In the case of the mutated form of rs4646155, the NOVA-1 protein induces an exon inclusion, while SLM-2 and Sam68 lead to intron exclusion. In the case of the mutated form of rs2106809, the hnRNP H proteins lead to an intron exclusion.

As COVID-19 emerged, it was postulated that SNPs in the ACE2 gene could affect susceptibility for SARS-CoV-2 infection (Darbani, 2020; Devaux et al., 2020; Hou et al., 2020). Particular attention was paid to the impact of the G₈₇₉₀A mutation on the severity of COVID-19, although its role in this disease remains controversial (Gómez et al., 2020; Möhlendick et al., 2021). About 77% of GG genotype, 13% of GA genotype and 9% of AA genotype were found in Caucasian SARS-CoV-2-positive patients and 70% of GG genotype, 14% of GA genotype and 16% of AA genotype carriers in SARS-CoV-2-negative people, respectively. A meta-analysis concluded that the ACE2 variant rs190509934:C (a rare variant) characterized by a lower ACE2 expression in individuals carrying the C allele, reduces the risk of SARS-CoV-2 infection (Horowitz et al., 2021).

Analysis of inter-individual ACE2 polymorphism, based on broad genomic databases reveal a link with the susceptibility to SARS-CoV-2 and the severity of COVID-19 (Brest et al., 2020; Cao et al., 2020). The pioneering work by Cao and colleagues identified 15 unique expression quantitative trait loci variants (14 SNPs and 1 InDel) with a higher frequency of minor alleles in the Asian population than in the European population. For example, the rs143695310 variant among East Asian populations was found to be associated with elevated expression of ACE2. Moreover, it was reported that Asian men have a higher ACE2 mRNA expression in their lungs than women, and that Asian people express higher amount of ACE2 than Caucasian and African American populations according to single-cell RNA-seq analysis (Zhao et al., 2020; Figure 4). Similar data were obtained using expression quantitative trait loci (eQTL), indicating a higher expression of ACE2 in South Asian and East Asian populations compared to Europeans, while the lowest expression levels were observed for Africans (Ortiz-Fernández and Sawalha, 2020). Dozen of human ACE2 variants were identified, which could impact on protein stability (e.g., Lys₂₆Arg, Gly₂₁₁Arg, and Asn₇₂₀Asp variants) or internalization (e.g., Leu₃₅₁Val and Pro₃₈₉His variants; Benetti et al., 2020; Cao et al., 2020; Othman et al., 2020). The rs41303171 C polymorphism, which is practically exclusive to Europeans (MAF 1.8%), is a missense SNP causing an Asn₇₂₀Asp replacement, which can trigger a conformational disorder in ACE2 changing viral interactions (Khayat et al., 2020). The Pro₃₈₉His variant occurs in Latino American population with an allele frequency of 0.015%. Only African Americans carry Met₃₈₃Thr and Asp₄₂₇Tyr variants with allele frequencies of 0.003 and 0.01%, respectively. The Arg₅₁₄Gly occurs in African Americans with an allele frequency of 0.003% (Hou et al., 2020). The European population with Arg₇₀₈Trp, Arg₇₁₀Cys, Arg₇₁₀His, or Arg₇₁₆Cys variants in mACE2 may have mild symptom of COVID-19 as ACE2 lose the cleavage site by TMPRSS2 (Hou et al., 2020; Lanjanian et al., 2021). The Ser₁₉Pro variant (rs73635825 genotype) common in African populations, may protect against COVID-19 while the Lys₂₆Arg variant (rs75548401 genotype) might predispose to severe forms of COVID-19 (Calcagnile et al., 2021). Recently, Suryamohan and colleagues found 298 unique ACE2 variants (Suryamohan et al., 2021). Among these variants they predicted that the Lys₃₁Arg polymorphism breaks an interaction with Gln₄₉₃ in the viral RBD and destabilizes the charge-neutralizing interaction with the virus and that the Glu₃₇Lys polymorphism disrupts the critical interactions with ACE2 Lys₃₅₃ by removing the polar intramolecular interaction that stabilizes contacts with the SARS-CoV-2 RBD. Similarly, the His₃₄Arg was predicted to result in a loss of interface polar contact. Thus, individuals carrying these variants are predicted to be less susceptible to SARS-CoV-2 infection. Fourteen human ACE2 variants (Ile₂₁Val, Glu₂₃Lys, Lys₂₆Arg, Asn₆₄Lys, Thr₉₂Ile, Gln₁₀₂Pro, Asp₂₀₆Gly, Gly₂₁₁Arg, Arg₂₁₉Cys, Glu₃₂₉Gly, His₃₇₈Arg, Val₄₄₇Phe, Ala₅₀₁Thr, and Asn₇₂₀Asp) which could enhance susceptibility to SARS-CoV-2 were found to have an higher allele frequencies in European populations than East Asian populations, while two additional ACE2 variants (Glu₃₅Lys and Phe₇₂Val) possibly conferring resistance to the virus, have higher allele frequencies in East Asian populations, while they are low or not expressed in European populations (Chen et al., 2021). Recently, a total of 570 genetic variations (SNP and InDel) on the ACE2 gene were reported in the Iranian population (Lanjanian et al., 2021).

Figure 4

ACE2 production and regulation inside human cells

Angiotensin-converting enzyme 2 surface abundance differ among cell types, indicating a complex epigenetic regulation of the ACE2 gene. The interaction between tissue or cell type specific enhancer/repressor is required for gene expression (Andersson et al., 2014). The ACE2 gene expression is also increased in individuals with pulmonary arterial hypertension, chronic obstructive pulmonary disease, obesity, diabetes, and older people (Muus et al., 2020; Pinto et al., 2020). In patients with hypertensive cardiopathy a marked ACE upregulation and ACE2 downregulation associated with Ang II/AT1R induced activation of the ERK1/2 and p38 MAP kinase, was reported (Koka et al., 2008). DNA methylation (5mC) was found to be involved in the silencing of ACE2 gene expression and CpG methylation was greater in patients with hypertension compared to healthy controls (Fan et al., 2017; Chlamydas et al., 2020; Cardenas et al., 2021). In contrast, enhanced ACE2 expression might also be protective in COVID-19 if it increases the peptidase activity of ACE2 thereby reducing Ang II concentration. Hypomethylation of specific sites in the ACE2 promoter was reported to correlate with increased ACE2 gene expression (Corley and Ndhlovu, 2020). Three CpGs (cg04013915, cg08559914, and cg03536816) at the ACE2 gene were reported as having lower methylation in lung epithelial cells compared to the other tissues (Beacon et al., 2021). The search for ACE2 topologically associating domains (TADs) with active histone markers, including H3 acetylated at K27 (H3K27ac) and H3 trimethylated at K4 (H3K4me3) or repressive histone markers (H3K27me3), revealed the presence of H3K4me3 at the promoter and after the first exon of ACE2, and the presence of H3K27ac in human kidneys (Beacon et al., 2021). The association of H3K4me3 correlates with ACE2 gene expression in the kidneys, heart, and small intestine. In contrast, H3K4me3 peaks are not detected in lung tissues.

MicroRNAs (miRNAs) are non-coding RNAs which can bind the 3′-untranslated regions (3’-UTRs) of target mRNAs, thereby regulating gene expression at a post-transcriptional level. Lysine-specific demethylase 5B, JARID1B, is responsible for the downregulation of several miRNAs that target ACE2 (Henzinger et al., 2020). Putative miRNA-binding sites were identified in the 3′-UTR of the ACE2 transcript thereby repressing translation. Both the miR-421, an miRNA implicated in the development of thrombosis and the miR-200c-3p were found to downregulate the ACE2 mRNA expression (Hirano and Murakami, 2020). In contrast the increases ACE2 mRNA expression (Sato et al., 2013; Siddiquee et al., 2013; Zhang et al., 2017). Other miRNAs predicted to bind to ACE2 mRNA 3’-UTR, such as miR-9-5p and miR-218-5p, were found to be differentially expressed in different cell types (Pierce et al., 2020). Moreover, the repression of the Xu and Li, 2021; Figure 5).An in silico studies aimed at predicting miRNAs that regulate ACE2-related networks with a possible impact on COVID-19 outcome, suggests that the top miRNAs regulating ACE2 networks are miR-27a-3p, miR-26b-5p, miR-10b-5p, miR-302c-5p, hsa-miR-587, hsa-miR-1305, hsa-miR-200b-3p, hsa-miR-124-3p, and hsa-miR-16-5p (Wicik et al., 2020). sACE2 shed into systemic circulation maintains its ability to generate Ang-(1–7). This process is fine-tuned by ADAM17 (also known as TACE), the metalloprotease ADAM10, and the transmembrane protease serine 2 (TMPRSS2), but only TMPRSS2 increases the entry of both SARS-CoV-1 and SARS-CoV-2 into susceptible cells (Lambert et al., 2005; Heurich et al., 2014; Hoffmann et al., 2020; Qiao et al., 2021). The ADAM17 and ADAM10 sheddases can trigger ACE2 ectodomain shedding by cleavage between amino acids 716 and 741 near the predicted transmembrane domain (Xiao et al., 2014), while TMPRSS2 trigger cleavage between amino acids 697 and 716 (Lanjanian et al., 2021). Phorbol ester and ionomycin as well as the proinflammatory cytokines IL-1β and TNF-alpha, can induce cellular proteases to catalyze sACE2 shedding (Jia et al., 2009). A study of plasma samples from 534 subjects indicated that up to 67% of the phenotypic variation in sACE2 shedding could be accounted for by genetic factors (Rice et al., 2006). mACE2 also interacts with several PDZ-binding proteins such as NHERF, involved in the internalization and recycling of mACE2 (Zhang et al., 2021). The in silico study of proteins belonging to the ACE2 interactome and which could be affected by SARS-CoV-2 infection, highlighted that the most affected interactions were associated with microtubule-associated serine and threonine kinase 2 (MAST2), and [Calmodulin 1 (CALM1; Wicik et al., 2020]. It was previously reported that CALM1 inhibitors increase sACE2 shedding by preventing calmodulin binding to the cytoplasmic tail of mACE2 (Lambert et al., 2008).

Figure 5

ACE2 through the ages

Structural comparisons of genes indicated that ACE2 and ACE arose by duplication from a common ancestor (Riordan, 2003). Although the evolutionary tree of ACE2 genes from 36 representative vertebrates is consistent with the species evolutionary tree, certain differences found in coelacanths and frogs may suggest a very slow evolutionary rate in the initial evolution of ACE2 in vertebrates (Lv et al., 2018; Damas et al., 2020; Lam et al., 2020; Luan et al., 2020; Lubbe et al., 2020; Liu et al., 2021). Orthologs of ACE2 and ACE also exist in bacteria, chordates and tunicates, suggesting an early origin of the RAS (Fournier et al., 2012). Although intriguing, the observation that the ACE2-like carbopeptidase from Paenibacillus sp. B38 catalyzes the conversion of Ang II to Ang-(1–7) and can suppress Ang II-induced hypertension, cardiac hypertrophy, and fibrosis in mice does not necessarily mean that the origin of the RAS goes back to bacteria but that a molecule with an ACE2-like carbopeptidase activity was maintained during speciation (Minato et al., 2020). ACE2-ancestors may then have acquired important new functions in tissues during speciation, as evidenced in humans. Beside the ACE2-like carbopeptidase, bacteria also express the neutral amino acid transporter SLC6A19, the homologous of B⁰AT1 in human, suggesting that SLC6A19 and the bacterial ACE2 ortholog may have already been molecular partners in bacteria (Gallucio et al., 2020). It is remarkable to note that an ACE-like bacterial protein named XcACE from Xanthomonas axonopodis pv. citri, hydrolyses Ang I into Ang II (Rivière et al., 2007). Other bacteria belonging to Lactococcus (L. lactis, L. helveticus, L. acidophilus, and L. casei) and Bifidobacterium species, release peptides with in vitro ACE-inhibitory activity (Fuglsang et al., 2003; Donkor et al., 2007).

The Ance genes from Drosophila melanogaster shares similarities with the human ACE2 (Burnham et al., 2005). In Acyrthrosiphon pisum, expression of the insect ACE2-ortholog is inducible upon feeding (Wang et al., 2015). The simultaneous KO of A. pisum ACE2 and ACE resulted in enhanced feeding and increased aphid mortality. It was also reported that the challenging of Anopheles gambiae with Staphylococcus aureus and Staphylococcus typhimurium upregulated the transcription of the Anopheles homolog of ACE, named AnoACE (Aguilar et al., 2005). Moreover, it was reported that treatment of A. gambiae with an ACE inhibitor resulted in larval death (Abu Hasan et al., 2017).

While searching for the zoonotic origin of SARS-CoV-2, special attention has been drawn to bats, minks and hamsters ACE2 molecules, as they might serve as viral receptors. Using multiple sequence alignments, we found that the bat ACE2 protein polymorphism grouped in the dendrogram according to the 18 subspecies of bats studied (Devaux et al., 2021c). The ACE2 from Rhinolophus bats appeared to be an appropriate candidate for interacting with SARS-CoV-2-related viruses, despite species polymorphism (i.e., R. sinicus with Lys₃₁, Tyr₄₁His, Asn₈₂, Asn₉₀, and Lys₃₅₃). The Lys₃₁Asp variant found in R. ferrumequinum may possibly alter the binding of the SARS-CoV-2 spike to the bat mACE2 receptor. The mACE2 sequences from other bat species showed increasing amino acid substitutions at positions considered to be required for SARS-CoV-2 spike binding (e.g., D. rotundus with Lys₃₁Asn, Tyr₄₁, Asn₈₂Thr, Asn₉₀Asp., and Lys₃₅₃Asn). The mACE2 proteins from Myotis bats examined were characterized by Lys₃₁Asn, Tyr₄₁His, Asn₈₂Thr, Asn₉₀, and Lys₃₅₃, including substitutions incompatible with SARS-CoV-2-like viruses binding. Regarding the ACE2 from minks we found that the mink ACE2 sequences from Neovison vison and Mustela lutreola displayed 99.51% similarity to one another, but shared only 83.73 and 83.48% amino acid identity with the human ACE2, respectively (Devaux et al., 2021b). The similarity between human ACE2 and mink ACE2 dropped to 63.34% in the region described to be involved in the interaction with the SARS-CoV-2 spike protein (regions 30–41, 82–93, and 353–358). Despite the fact that more than 130 substitutions out of 805 amino acids were observed between the human ACE2 and mink ACE2 (e.g., 131 substitutions and 133 substitutions for N. vison ACE2 and M. lutreola ACE2, respectively), including an Asn₉₀Asp substitution possibly impacting the affinity of mink ACE2 for the virus, the Lys₃₁, Tyr₄₁, and Lys₃₅₃ amino acids required for human ACE2 interaction with the SARS-CoV-2 spike protein are conserved in minks mACE2. This amino acids triad is also conserved in hamsters. The Figure 6A, illustrates a comparison of ACE2 amino acid sequences from humans, mink, hamsters, mice and bats.

Figure 6

ACE2 as SARS-CoV-2 receptor

Severe acute respiratory syndrome coronavirus is an enveloped single-stranded positive-sense RNA virus (its genome contains ∼32 kb). The SARS-CoV-2 viral envelope consists of a lipid bilayer, where the viral membrane (M), envelope (E), and spike (S) structural proteins are anchored. The S proteins surrounding the viral particles consist of two subunits, S1 and S2. This S protein determines the cellular tropism of the virus. In 2020, ACE2 was identified as the main entry receptor for the SARS-CoV-2 virus (Zhao et al., 2020; Zhuang et al., 2020; Baggen et al., 2021). SARS-CoV-2 is the third human coronavirus after SARS-CoV-1 and HCoV-NL63 which use the human mACE2 as a cellular receptor (Li et al., 2003, 2007). A unique feature of SARS-CoV-2 compared with SARS-CoV-1 is the presence of a polybasic motif (RRAR) at the S1/S2 boundary, which can be cleaved by furin (Walls et al., 2020), resulting in a C-terminally exposed RRAR peptide. Two independent studies showed that this peptide directly binds to neuropilin-1 (NRP1) and that NRP1 promotes SARS-CoV-2 infection (Cantuti-Castelvetri et al., 2020; Daly et al., 2020).

A critical step in the SARS-CoV-2 infection cycle is the binding of the homotrimeric viral spike protein through RBD to the peptidase domain of mACE2 (Lan et al., 2020; Shang et al., 2020; Yan et al., 2020). Despite high similarity between the RBD of SARS-CoV-1 and SARS-CoV-2, several amino acid variations in the binding domain of SARS-CoV-2, increase its affinity for ACE2 (Lan et al., 2020; Yan et al., 2020). The interaction is driven by two domains in the S1 subunit of the molecule, namely the RBD and the N-terminal domain (NTD). The NTD displays a flat electropositive ganglioside binding site enabling the virus to interact with lipid rafts of the cell membrane (Fantini et al., 2021). At the N terminus of the viral spike, Gln₄₉₈, Thr₅₀₀, and Asn₅₀₁ of the RBD form a network of H-bonds with Tyr₄₁, Gln₄₂, Lys₃₅₃, and Arg₃₅₇ of the human mACE2. In addition, in the middle of the bridge, Lys₄₁₇ and Tyr₄₅₃ of the RBD interact with Asp₃₀ and His₃₄ of ACE2, respectively. Moreover, Gln₄₇₄ of the RBD is H-bonded to Gln₂₄ of ACE2, whereas Phe₄₈₆ of the RBD interacts with Met₈₂ of ACE2 through van der Waals forces (Yan et al., 2020). Binding of S1 to the mACE2 receptor triggers an ACE2 ectodomain cleavage by ADAM17 (Lambert et al., 2005; Heurich et al., 2014; Oarhe et al., 2015). The ACE2 cleavages by ADAM17 and a serine protease (TMPRSS2 or TMPRSS4) induce the shedding of cellular ACE2 and systemic release of S1/sACE2 complex, and primes for cellular viral entry (Hoffmann et al., 2020). When S1 binds to mACE2, another site on S2 is exposed and cleaved by host proteases. S2 does not interact with mACE2 but harbors the functional elements which guides membrane fusion. So, SARS-CoV-2 can therefore utilize two pathways to infected ACE2 positive cells: the virus can either fuse at the plasma membrane (early pathway) or, it can fuse at the endosomal membrane (late pathway). The privileged pathway is determined by the proteases present at the cell membrane (Wicik et al., 2020; Caillet-Saguy and Wolf, 2021). When the fusion occurs at the cell membrane, this process is followed by the formation of a funnel like structure built by two heptad repeats in the S2 protein in an antiparallel six-helix bundle, facilitating the fusion and release of the viral genome into the cytoplasm. When the protease is absent, SARS-CoV-2 can be endocytosed via clathrin-and non-clathrin-mediated internalization and the virion is then activated in endosomal vesicles by the action of low pH-dependant protease Cathepsin L (Tang et al., 2020). Thus, the expression and polymorphism of both ACE2 and TMPRSS2 are likely to dictate SARS-CoV-2 tissue tropism (Hou et al., 2020; Zou et al., 2020). Whether overexpression of mACE2 would facilitate infection (increasing the number of receptors available for the virus) or restrict the risks of developing the most severe forms of the disease, has long been a source of controversy (Vaduganathan et al., 2020). Once bound to mACE2, SARS-CoV-2 down-regulates the cellular expression of the ACE2 gene and mACE2 protein and the unopposed action of Ang II was deemed responsible for worsening the outcome of COVID-19 (Hendren et al., 2020).

The ACE2 key residues at the ACE2/S-protein-RBD interface include Ser₁₉, Gln₂₄, Thr₂₇, Phe₂₈, Asp₃₀, Lys₃₁, His₃₄, Glu₃₅, Glu₃₇, Asp₃₈, Tyr₄₁, Gln₄₂, Leu₄₅, Leu₇₉, Met₈₂, Tyr₈₃, Thr₃₂₄, Gln₃₂₅, Gly₃₂₆, Glu₃₂₉, Asn₃₃₀, Lys₃₅₃, Gly₃₅₄, Asp₃₅₅, Arg₃₅₇, Pro₃₈₉, and Arg₃₉₃ (Suryamohan et al., 2021). The Lys₃₁ and Lys₃₅₃ residues in human mACE2 form hydrogen bonds with the main chain of Asn₅₀₁ and Gln₄₉₃ in the RBD. ACE2 variants Ser₁₉Pro, Ile₂₁Val, Glu₂₃Lys, and Lys₂₆Arg (which stabilizes core ACE2 α-helical interactions), Thr₂₇Ala (which removes interactions between Thr₂₇ and Glu₃₀), Asn₆₄Lys, Thr₉₂Ile, Gln₁₀₂Pro and His₃₇₈Arg were predicted to increase cell susceptibility to SARS-CoV-2. In contrast, ACE2 variants Lys₃₁Arg (which breaks an interaction with Gln₄₉₃ in the SARS-CoV-2 spike RBD), Asn₃₃Ile, His₃₄Arg (which results in a loss polar contact at the interface with SARS-CoV-2 spike RBD), Glu₃₅Lys (which affects the critical polar contact with SARS-CoV-2 spike Gln₄₉₃), Glu₃₇Lys, Asp₃₈Val (which compromises the Asp₃₈-Lys₃₅₃ interaction), Tyr₅₀Phe, Asn₅₁Ser, Met₆₂Val, Lys₆₈Glu, Phe₇₂Val, and Tyr₈₃His (which prevents insertion of SARS-CoV-2 spike residue Phe₄₈₆ into an hydrophobic pocket driven by residue Tyr₈₃), Gly₃₂₆Glu, Gly₃₅₂Val, Asp₃₅₅Asn, Gln₃₈₈Leu, and Asp₅₀₉Tyr were predicted to be less sensitive to SARS-CoV-2 (Procko, 2020; Suryamohan et al., 2021). When considering ACE2 variants, high mACE2 cell-surface expression can mask the effects of impaired binding while low cell surface expression reveals a range of infection efficiencies across variants, supporting a major role for binding avidity during viral entry (Shukla et al., 2021). Using an in vitro model of infection of cells expressing suboptimal surface ACE2, it was found that the mACE2 variants Asp₃₅₅Asn, Arg₃₅₇Ala, and Arg₃₅₇Thr abrogated entry of SARS-CoV-2 while Tyr₄₁Ala showed only a slight effect on SARS-CoV-2 entry although it inhibited SARS-CoV-1. The NTD and RBD domains in the viral S protein act synergistically to insure virus adhesion (Fantini et al., 2021). Moreover, an inverse correlation was established between ACE2 expression and COVID-19 severity (Chen et al., 2021).

Particular attention was drawn to polymorphism of ACE2 in bat (considered to be a reservoir of SARS-CoV-related virus; Zhou et al., 2020; Wacharapluesadee et al., 2021) this species, and in minks (because they have been shown to be susceptible to infection by SARS-CoV-2 from humans and then to be a source of the virus being able to reinfect humans; Boklund et al., 2021; Oude Munnink et al., 2021; Shuai et al., 2021). It was found that when SARS-CoV-2 of human origin become host-adapted to mink, a Tyr₄₅₃Phe substitution located in the RBD was selected. This process is driven by the fact that mink mACE2 has a Tyr₃₄ instead of the H₃₄ found in human mACE2 and that the Tyr₄₅₃Phe substitution improves the virus binding to the mink mACE2 (Ren et al., 2021). The hamster is another species of interest for ACE2, because hamster-adapted SARS-CoV-2 Delta variants were isolated in Hong Kong, and the virus was transmitted back to human and further human-to-human transmission was then demonstrated (Kok et al., 2022; Yen et al., 2022). We found that once adapted to the hamster ACE2, the variant virus show mutations (e.g., Asp₄₂₇Gly) that could make this virus more efficient at infecting humans (Fantini et al., 2022). Although a large number of animal species were considered to be susceptible to infection by SARS-CoV-2 (Stawiski et al., 2020), SARS-CoV-2 (Wuhan-HU1 strain) cannot use mouse ACE2 (Zhou et al., 2020). The presence of Asn₃₀ (instead of Asp₃₀) and Asn₃₁ (instead of Lys₃₁) in mouse ACE2 is likely to cause the lack of salt bridges and the critical H-bond at the mouseACE2-SARS-COV-2 RBD interface. In addition, the presence of His₃₅₃ (instead of Lys₃₅₃), leads to unfavorable interactions with the SARS-CoV-2 S protein RBD (Brooke and Prischi, 2020; Gao and Zhang, 2020). However, this does not rule out the possibility of low efficiency mouse infection through an alternative receptor. It was reported that the expression of human basigin/CD147 in mice, enabled SARS-CoV-2 infection with detectable viral loads in the lungs (Wang et al., 2020). However, this model remains controversial (Shilts et al., 2021). It has been reported that the B1.1.7 (20I/501Y.V1; United Kingdom variant), B.1.351 (20H/501Y.V2; South Africa variant), and P1 (20J/501Y.V3; Brazilian variant) SARS-CoV-2 variants and other N501Y-carrying variants exhibit extended host ranges to mice (Montagutelli et al., 2021; Shuai et al., 2021). Moreover, it has been postulated that the new lineage SARS-CoV-2 Omicron variant (BA.1, BA.2), has a murine origin (Wei et al., 2021). Indeed, the interspecies conservation of ACE2 turns out to be sufficient to allow viruses that use this receptor to circulate between animal hosts and humans. Viruses do not spread based on species but based on their ability to recognize a receptor and circumvent the host immune defenses. We have proposed that this general principle accounts for the circulation of SARS-CoV-2 between species (Frutos et al., 2021, 2022; Figure 6B).

Immune response against SARS-CoV-2 and auto-antibodies against ACE2 in COVID-19 patients

Infection with SARS-CoV-2 initiates an antiviral immunoglobulin (Ig)M and IgA response, detectable during the first week of symptoms, whereas IgG are found later. The antibody titres reaches a plateau within 6 days after seroconversion (Guo et al., 2020; Kellam and Barclay, 2020; Long et al., 2020; Zhao et al., 2020). The serum level of SARS-CoV-2 specific IgA is positively correlated with the severity of COVID-19 (Ma et al., 2020; Yu et al., 2020). The state of hyperstimulation of the immune system that occurs in severely ill patients contributes to autoimmune manifestations and is associated with an increased need for oxygen therapy (Gagiannis et al., 2020). Moreover, it was recently reported that Ang II induces ROS release from monocytes able to induce DNA damages and apoptosis in neighboring T-cells leading to lymphopenia in certain patients with severe forms of COVID-19 (Kundura et al., 2022). It is neither the purpose of this paragraph to discuss the complex pattern of immune response in COVID-19 (e.g., a decrease in the total number of CD4+ and CD8+ T cells, B cells, and NK and a recruitment of neutrophils; a massive increase in the release of inflammatory cytokines or ‘cytokine storm’, and chemokines such as IL-2, IL6, IL-7, IL-8, IL-10, TNF, IFN; Amor et al., 2020; Campbell and Kahwash, 2020; Han et al., 2020; Luo et al., 2020; Mehta et al., 2020; Tay et al., 2020; Vitte et al., 2020; Zheng et al., 2020), nor is it to review the abnormal expression of Ag II in COVID-19 patients that could stimulate proinflammatory processes (Naftilan and Oparil, 1978; Moore et al., 2015; Varanat et al., 2017; Silva et al., 2020; Raghavan et al., 2021; Vandestienne et al., 2021; Yamamoto et al., 2021), but rather to briefly summarize the contribution of anti-ACE2 and anti-AT1R auto-antibodies in COVID-19, since these molecules could play an important role in the immunological puzzle of clinical variability of the disease.

What was intriguing in SARS-CoV-2 infected patients with respect to the RAS, was the report of the development of ACE2 auto-antibodies. Among 53 patients who had detectable anti-SARS-CoV-2 RBD, 40 (75%) had anti-ACE2 antibodies (Arthur et al., 2021). Among them, 26 (81%) belonged to the convalescent group and 14 (15; 93%) were patients hospitalized for symptoms of COVID-19. Healthy controls with no history of SARS-CoV-2 were all negative for anti-ACE2 antibodies. The median activity of sACE2 in patients with ACE2 auto-antibodies was 263 pmol/min/ml compared to 1,056 pmol/min/ml for those who did not develop an anti-ACE2 immune response. The binding of anti-ACE2 antibodies to ACE2 in normal cells could have the potential to mediate profound pathophysiological effects long after the original antigen itself has disappeared, particularly in the long term COVID-19 patients (e.g., possibly inducing myocarditis or neurological illnesses; Figure 7).

Figure 7

Considering the similarities between vasculopathy in severe COVID-19 and antibody-mediated rejection after lung transplantation induced by auto-antibodies against AT1R (Cozzi et al., 2017), the presence of AT1R auto-antibodies in COVID-19 patients was investigated and compared to patients with a favorable disease course. A significant increase (42%) of anti-AT1R Ig was found in COVID-19 patients with an unfavorable disease course (Miedema et al., 2021). These AT1R auto-antibodies are expected to mimick the proinflammatory effect of Ang II, as previously reported (Dragun et al., 2005). Tissue transglutaminase (TG2)-mediated modification of AT1R contributes to AT1R auto-antibody production and hypertension associated with preeclampsia; the post-translational modification of Gln₁₈₇ in the second extracellular loop of the AT1R loop creates a neo-epitope that induces the production of an autoantibody that can activate the receptor (Liu et al., 2015). Endothelin receptor type A (ETAR) auto-antibodies were also more frequent in severe COVID-19 patients (Miedema et al., 2021). These antibodies are known to stimulate chemotactic activity and neutrophils trafficking (Cabral-Marques et al., 2018). Both anti-AT1R and anti-ETAR antibodies could be associated with cardiovascular disease and hypertension in severe COVID-19 patients (Philogene et al., 2019).

Among other auto-antibodies found in COVID-19 patients, anti-interferon Ig was found in patients with severe COVID-19 while no such auto-antibodies were found in patients with mild disease (Bastard et al., 2020). Anti-phospholipid antibodies have also been observed as being associated with thrombotic events in COVID-19 cases (Bertin et al., 2020; Daviet et al., 2020; Harzallah et al., 2020; Helms et al., 2020; Manne et al., 2020; Siguret et al., 2020; Tan et al., 2020; Xiao et al., 2020; Zhang Y. et al., 2020; Zuo et al., 2020; Brodard et al., 2021).

SARS-CoV-2 triggers a vascular and coagulation disease

Venous thromboembolism is a relatively common side effect of SARS-CoV-2 infection. It is characterized by an acute pulmonary embolism or intravascular coagulopathy that predisposes the patients to thrombotic events (Faggiano et al., 2020; Leonard-Lorant et al., 2020; Middeldorp et al., 2020). After the first month of infection, individuals with COVID-19 are at an increased risk of cardiovascular disease, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure, and thromboembolic disease (Xie et al., 2022). A nationwide cohort found an increased risk of a deep vein thrombosis up to 3 months after COVID-19, pulmonary embolisms up to 6 months, and bleeding events up to 2 months, with the risk of pulmonary embolism being especially high (Katsoularis et al., 2022). Elevated D-dimers (which reflects the degradation of fibrin and a process of hypercoagulation) upon admission of patients is a marker of hypercoagulation and pulmonary embolism and is associated with increased mortality in severe COVID-19 patients (Lippi and Favaloro, 2020; Sakka et al., 2020; Stefely et al., 2020; Smadja et al., 2021). High levels of D-dimers are found in ∼ 20–40% of critically ill COVID-19 patients (Poissy et al., 2020; Zhang Y. et al., 2020; Zhang S. et al., 2020; Xie et al., 2022). Usual thrombosis prophylaxis is often not sufficient to prevent thrombotic coagulopathy in patients with severe forms of COVID-19 (Berthelot et al., 2020). These lesions usually start with intimal proliferation, followed by fragmented and discontinuous internal elastic lamina (Carvelli et al., 2020; Hofman et al., 2021). Perivascular inflammation was reported to be patchy and scattered, composed mainly of lymphocytes, with thrombi in the branches of the pulmonary artery and focal areas of congestion in the alveolar septal capillaries, as well as septal capillary lesions with wall and luminal fibrin deposition (Deshmukh et al., 2020).

The pathological manifestation of COVID-19 has a strong vascular component, with exacerbated effects on the microvasculature comprising the arterioles, capillaries, venules, and microthrombosis events. The increased occurrence of microvascular thrombi provides a good explanation for the sometimes sudden development of hypoxemia in COVID-19 patients, since the thrombi prevent gas exchange in the oxygenated areas of tissues. Beside the formation of fibrin thrombi, ARDS is characterized by increased alveolar capillary permeability and exudation into the alveoli, where inflammatory cells are present in abundance, as well as coagulation factors including fibrinogen. Regarding COVID-19, it was suggested to name severe pulmonary COVID-19 as “MicroCLOTs” for “microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome” (Ciceri et al., 2020). The analysis of autopsy lung specimens from COVID-19 patients has shown inflammatory perivascular lymphocyte infiltration, the presence of microvascular thrombi containing platelets, fibrin and numerous neutrophil extracellular traps (NETs) releasing (Carsana et al., 2020; Hofman et al., 2021). Deposits of complement components C3, C4d and C5b-9 were found in the microvasculature of the lungs (Magro et al., 2020). Patients diagnosed with elevated D-dimer and thrombosis during severe forms of COVID-19 have higher blood levels of markers of NETs and calprotectin (Zuo et al., 2020). The formation of NETs in turn, perpetuates complement activation. When activated by proinflammatory cytokines, or NETs, the vascular endothelial cells produce von Willebrand factor (vWF) that retains platelets and leucocytes to the vessel wall and activates coagulation leading to the repair of local damage. Finally, microangiopathic vessel occlusions and endothelium damage has been described in the kidneys (Goshua et al., 2020).

Among the mechanisms implicated in this thrombo-inflammation, AngII seems to have pleiotropic effects. Indeed, regarding the central role played by ACE2 as the viral entry receptor, and its role in the regulation of Ang II blood levels, the balance between ACE2 expression and the accumulation of Ang II in the blood stream may contribute to explain the immunothrombosis. The analysis of RAS dysfunction and Ang II side effects is critical for the understanding of the pathophysiological changes due to SARS-CoV-2 infection. Ang II has a significant effect on the platelet and coagulation/fibrinolytic system and causes mild activation of the coagulation cascade with increases in plasma levels of the thrombin–antithrombin complex and prothrombin (Brown and Vaughan, 2000; Larsson et al., 2000; Fletcher-Sandersjöö and Bellander, 2020; Gando and Wada, 2021). The platelet activation described after COVID-19 is thought to be due in part to the binding of AngII to AT1R. Moreover, SARS-CoV-2 can directly activate platelets by binding to platelet ACE2 (Zhang S. et al., 2020). Through binding to AT1R, Ang II stimulates the expression of Tissue Factor (TF), which triggers coagulation cascade (Nemerson, 1988; Nishimura et al., 1997; Muller et al., 2000; Felmeden et al., 2003; He et al., 2006; Brambilla et al., 2018). Ang II also induces expression of plasminogen activator inhibitor-1(PAI-1), the main inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, in cultured endothelial cells (Fogari et al., 2011). Increased levels of PAI-1 can occur locally upon SARS-CoV-2 infection, leading to the formation of plugs in the body.

The binding of SARS-Cov2 to ACE2 at the surface of endothelial cells (ECs) of blood and lymph vessels, leads to activation of the complement system, promoting a pro-coagulative state, leukocyte infiltration, vascular dysfunction, and thrombosis (Jin et al., 2020). In severe COVID-19 patients, the plasma levels intercellular adhesion molecule 1 (I-CAM-1), vascular cell adhesion molecule-1 (VCAM-1), and vascular adhesion protein-1 (VAP-1), are elevated (Escher et al., 2020; Tong et al., 2020), indicating that the endothelial barrier is damaged consecutive to viral infection. Soluble E-selectin, soluble ICAM-1, and soluble platelet endothelial adhesion molecule 1 (sPECAM-1) correlate with disease severity (Li et al., 2021; Vassiliou et al., 2021). ICAM-1 promotes fibrin adhesion and leukocyte transmigration and increased thrombus formation. Disruption of the vascular barrier is associated with the inhibition of protein C, a major anticoagulant (Dahlbäck and Villoutreix, 2005). The plasma levels of vWF, angiopoietin-2, Fms-related tyrosine kinase 3 ligand (FLT-3L), and PAI-1 are significantly elevated in patients with COVID-19 (Liu and Zhang, 2021; Figure 8). Moreover, a decrease ADAMTS13, which ensure vWF hemostatic function, has been reported in severe forms of COVID-19 (Bazzan et al., 2020; Rodriguez Rodriguez et al., 2021). It was also reported that the SARS-CoV-2 main protease M^pro causes microvascular brain pathology by cleaving NEMO (an essential modulator of NF-κB) in infected brain ECs (Wenzel et al., 2021).

Figure 8

In response to COVID-19, the activation of ECs was also associated with the overexpression of proangiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2), and placental growth factors (PlGF; Smadja et al., 2021). Soluble Flt-1 (sFlt-1), a circulating truncated form of the VEGF-A receptor, was markedly increased in severe forms of COVID-19 (Rovas et al., 2020). Damage to ACE2+ pericytes and ECs leads to vascular permeability in severe COVID-19 (Cardot-Leccia et al., 2020; Afzali et al., 2021). The viral Spike induces oxidative stress, ERK1/2 activation through the CD147 receptor and NF-κB nuclear translocation in pericytes, thereby prompting dysfunction of the vascular pericytes (Avolio et al., 2021; Khaddaj-Mallat et al., 2021). CD147, considered to have a potential proatherosclerotic effect (Wang et al., 2015), is upregulated in COVID-19 patients and can act as a receptor for SARS-CoV-2 in cells expressing low ACE2 (Radzikowska et al., 2020). Interestingly, statins, the action of which partly relies on CD147 downregulation, have been recommended in the therapeutic arsenal against COVID-19 (Zhang X.J. et al., 2020).

Modulation of ACE2 and other actors of the RAS in COVID-19 patients

Coronavirus disease 2019 is a systemic disease characterized by a cytokine storm associated with high levels of C reactive protein (CRP), high fibrinogen, high fibrin degradation to D-Dimers, microvascular injury, and obstructive thrombo-inflammatory syndrome. As knowledge grows, the need for a deeper understanding of the molecular cross-talk leading to thrombosis appears as a research priority in order to gain a better understanding of ARDS and MODS associated with severe COVID-19.

In a pioneer study it was demonstrated that SARS-CoV-1 infection was associated with ACE2 downregulation and impaired degradation of Ang II (Kuba et al., 2005). Since both SARS-CoV-1 and SAR-CoV-2 enter cells through ACE2 and induce simimlar diseases, attention rapidely focused on the consequences of virus-ACE2 interaction on the dysregulation of RAS. This is complexified by the fact that SARS-CoV-2 infection triggers IFN activation, which in turn can upregulate ACE2 (Garvin et al., 2020). Another element of complexity resides in the fact that a greater number of ACE2+ cells seems to circulate in the lungs of patients with severe COVID-19 (Ackermann et al., 2020). Using a swine animal model it was demonstrated that blocking ACE2 (or infusing Ang II) leads to increased pulmonary artery pressure, reduced blood oxygenation, increased coagulation, diffuse alveolar damage, and acute tubular necrosis (Aroor et al., 2016).

Despite efforts that have been made to quantify the compound of the RAS in COVID-19 patients, this exploration remained incomplete and debatable. An early study found no difference in the Ang II/Ang I ratio in the plasma sample of 31 COVID-19 patients, but reported that the plasma sACE2 activity was increased in patients treated with an ACE inhibitor (Kintscher et al., 2020). Another study reported increased plasma levels of Ang II in 12 patients with severe COVID-19 pneumonia (Liu et al., 2020). Furthermore, no alteration of RAS was found in a cohort of nonsevere COVID-19 patients (Rieder et al., 2021). More recently, a sevenfold ACE2 increase was found in patients with COVID-19 and Ang II as well as Ang-(1–7) concentrations was significantly higher in patients with severe COVID-19 (Reindl-Schwaighofer et al., 2021). Another investigation in a cohort of 306 COVID-19 patients revealed that elevated plasma sACE2 from COVID-19 patients was significantly associated with severe forms of disease, particularly in hospitalized patients intubated at the time of sample collection (Kragstrup et al., 2021). ARDS in patients with COVID-19 was found associated with an increase in blood pressure and decrease in serum potassium concentration (Vicenzi et al., 2020). Surprisingly, another recent report suggests a significant reduction of Ang II concentration and increased Ang-(1–7) in COVID-19 patients (Martins et al., 2021). The divergent results reported concerning the variation of RAS molecules in plasma from SARS-CoV-2-positive patients could either be explained by the differing severity of COVID-19 in the groups of patients tested and/or by the method used for quantification of the molecules (Figure 9).

Figure 9

Recently, by exploring different biomarkers in a cohort of COVID-19 patients (30 prolonged viral shedders and 14 short viral shedders) we found that circulating blood cells (in particular monocytes) from COVID-19 patients expressed less ACE2 mRNA than cells from healthy volunteers (Osman et al., 2021). Moreover, although we found the expression of sACE2 to be heterogenous among individuals from each group, the sACE2 plasma concentrations were found to be lower in prolonged viral shedders than in healthy controls, while the concentration of sACE2 returned to normal levels in short viral shedders. In the plasma of prolonged viral shedders, we also found higher concentrations of Ang II and Ang I. However, the plasma levels of Ang-(1–7) were found to be almost stable in prolonged viral shedders, but seemed insufficient to prevent the adverse effects of Ang II accumulation, strongly suggesting that increased levels of Ang II contribute to thrombotic events associated with the severe forms of COVID-19.

Targeting ACE2 for the therapeutic prevention of severe forms of COVID-19

In COVID-19 patients, the downregulation of ACE2 and the reduced capacity to counteract the detrimental effects of Ang II are likely to play a critical role in the development of severe forms of the disease. In experimental animal models, ACE2 KO mice experienced more severe forms of acute lung injury than wild type mice, highlighting the protective role of ACE2 (Imai et al., 2005). The loss of ACE2 resulted in enhanced vascular permeability, neutrophils accumulation and increased lung edema. Both angiotensinogen-specific antisense oligonucleotides and small interfering RNA (siRNA) lowered blood pressure in rat models of hypertension (Mullick et al., 2017; Uijl et al., 2019). In humans with weight excess and hypertension, renin inhibitors (e.g., aliskiren) and ACEi (e.g., ramipril), improve renal and systemic hemodynamics and reduce arterial pressure (Kwakernaak et al., 2017). Thus, therapeutic solutions for reducing COVID-19 severity could be found in the pharmacopeia used by cardiologists to intervene on the RAS.

All FDA approved drugs for treatment of patients with high blood pressure (renin inhibitors, ACEi, and ARBs) are primarily designed to block or reduce the detrimental effects of Ang II (Wright, 2000; Mentz et al., 2013; Arendse et al., 2019; Figure 10A). Reducing the formation of Ang II by ACEi or antagonizing its effect by blocking the AT1R through ARBs may be a suitable strategy for reducing symptoms of COVID-19 patients (Schiffrin et al., 2020). ARBs (e.g., losartan) were found to protect against acute lung injury through the reduction of Ang II/AT1R stimulation (Shen et al., 2009; Meng et al., 2020). Hypertensive patients taking ARBs presented a lower risk of severe COVID-19 (Sarzani et al., 2020). However, the interpretation of the benefits and harmful effects of ACEi and ARBs may be premature due to the multiple effects of such molecules on the RAS (Kai et al., 2021; Tereshchenko et al., 2022). Indeed, it has been reported that ACEi and ARBs increase ACE2 (Ferrario et al., 2005; Furuhashi et al., 2015), which could also increase the binding of SARS-CoV-2. However, it has been reported that ACE2 is not increased by ACEi or ARBS in the respiratory cilia (Lee et al., 2020). We recently reported that in vitro treatment of SARS-CoV-2 permissive ACE2+/AT1R+ Vero E6 cells with various ARBs resulted into ∼50% increase in SARS-CoV-2 production correlated with the ARBs-induced up-regulation of ACE2 expression (Pires de Souza et al., 2022). However, we also observed a downregulation of AT1R, suggesting that Ang II harmful effects should be strongly reduced (Pires de Souza et al., 2022). The upregulation of ACE2 can have opposed effects on SARS-CoV-2 infection and organ pathophysiology (Devaux, 2020). The study of large cohorts support the beneficial effects of RAS inhibitors in patients with COVID-19 (Bean et al., 2020; Zhang P. et al., 2020). In patients, ARBs is preferred over ACEi for first line hypertension treatment and discontinuing treatment is not required (Abbasi, 2021; Lopez et al., 2021). Since, the activation of AT1R by Ang II induces ROS through the NADPH oxidase pathway and activates the hypoxia-inducible factor (HIF)-1α leading to the synthesis of the transient receptor potential channel ankyrin repeat (TRPA1) which controls intracellular calcium increase and potentially contributes to pulmonary inflammation, it was also suggested to use calcium channel blokers as an alternative to ACEi and ARBS (Fang and Karakiulakis, 2020; Tignarelli et al., 2020; Devaux and Raoult, 2022; Zhang et al., 2022). Moreover, acting on HIF-1α, may improve the outcome of COVID-19 by decreasing hypoxia (Devaux and Raoult, 2022).

Figure 10

In silico methods of molecular docking have been used to develop allosteric activators of ACE2 such as xanthenone (XNT), the antiprotozoal dimiazene aceturate (DIZE) drug, and resorcinolnaphthalein (Hernández Prada et al., 2008; Gjymishka et al., 2010). Activation of ACE2 by XNT, prevented elevated right ventricular systolic pressure, ventricular hypertrophy, and increased pulmonary vessel wall thickness (Ferreira et al., 2009; Fraga-Silva Rodrigo et al., 2013; Cole-Jeffrey et al., 2015). DIZE was found to reduce the severity of hyperoxic lungs injury by inhibiting the inflammatory response and oxidative stress, to attenuate the myocardial infarction, and to prevent atherosclerosis by increasing ACE2 mRNA expression (Kulemina and Ostrov, 2011; Qi et al., 2013; Shenoy et al., 2013; Haber et al., 2014; Qiu et al., 2014; Goru et al., 2017; Fang et al., 2019; Qaradakhi and Gadanec, 2020). Various FDA-approved molecules are under study for evaluating their ability to reduce COVID-19 severity (Albini et al., 2020; Lubbe et al., 2020; Qaradakhi and Gadanec, 2020). For example, the virtual screening of 2,456 approved drugs as inhibitors of SARS-CoV-2 spike-ACE2 interaction highlighted the properties of riboflavin (a vitamin), fenoterol (a bronchodilator), vidaranine (an anti-neoplastic agent), and cangrelor (an anti-platelet agent; Prajapat et al., 2020).

A better understanding of the role of the ACE2, encouraged the use of human recombinant soluble ACE2 (hrsACE2) in medicine (Kuba et al., 2005; Oudit et al., 2010; Johnson et al., 2011). In a tolerability study in healthy volunteers, doses up to 1.2 mg/kg hrsACE2 were administered intraveinously and the plasma half-life of the molecule was in the range of 10 h (Haschke et al., 2013). Despite a fast clearance rate, the administration of hrsACE2 alleviated the severity of influenza A H7N9 and respiratory syncytial virus (RSV)-induced lung injury (Yang et al., 2014; Gu et al., 2016). This hrsACE2 was also found to reduce IL-6 when given to healthy volunteers suffering from ARDS (Khan et al., 2017; Zhang and Baker, 2017). Through its binding to the viral S protein, sACE2 could act as a decoy receptor and could reduce the harmful effect of Ang II by making mACE2 available for the conversion of Ang II (Patel et al., 2014; Devaux et al., 2020; Issa et al., 2021; Krishnamurthy et al., 2021). The infusion of a single dose of hrsACE2 (GSK2586881 at 0.4 mg/kg i.v.), was found to be well-tolerated and to have potential haemodynamic benefits in pulmonary arterial hypertension (Hemnes et al., 2018). A hrsACE2 clinical trial is ongoing (NCT00886353) for the treatment of cardiovascular diseases (Ghatage et al., 2021). It has been reported that ACE2 S₆₈₀D gain-function knock-in mice are protected against hypoxia-induced pulmonary hypertension (Zhang et al., 2018). This has also opened the way to modified ACE2 for gene transfer (Guignabert et al., 2018). It was recently demonstrated that recombinant ACE2 is effective for treating SARS-CoV-2 RBD protein-aggravated LPS-induced acute lung injury in a mouse experimental model and that the protection occurs by acting on the ACE2-AngII-AT1R-NOX1/2 axis that is otherwise overactivated by the SARS-CoV-2 infection (Zhang et al., 2022).

A proof-of-concept of the efficiency of the hrsACE2 therapeutic approach in COVID-19 was described in a case report of a 45-year-old woman infected by SARS-CoV-2 who was admitted to hospital with a 7-day history of severe symptoms. Two days after hospital admission, she was treated with 0.4 mg/kg of hrsACE2 intravenous infusion twice daily. Surprisingly after the first injection the patient became afebrile, the biological investigation indicated a marked reduction of Ang II, an increase of sACE2 in plasma, and her clinical condition improved gradually (Zoufaly et al., 2020). A large phase II clinical trial has been initiated by the Austrian pharmaceutical company APEIRON to treat COVID-19 patients with APN01-rhACE2. More recently, hrsACE2, in combination with sub-toxic remdesivir, was found to reduce viral load by 60% in a model of SARS-CoV-2 infected kidney organoids (Monteil et al., 2021).

Given such encouraging results, it seemed important to design molecules with improved activity against SARS-CoV-2 (Maiti, 2021; Figure 10B) A fusion molecule consisting of murine rACE2 with a Fc fragment (rACE2-Fc), demonstrated a long-lasting ability to protect organs in mice models of Ang II-dependent hypertension (Liu et al., 2018). It was also reported that Lactobacillus paracasi probiotic expressing a hrACE2 extracellular domain in fusion with the nontoxic subunit B of cholera toxin, resulted in increased ACE2 activities in serum of mice treated with this compound (Verma et al., 2019). Another molecule, rACE2 extracellular domain fused to the FC region of the IgG1, has been shown to neutralize viruses pseudotyped with SARS-CoV-2 spike proteins in vitro (Lei et al., 2020). A new set of molecules named “ACE2 receptor trap” that contain the extracellular domain residues 18–614 (including the SARS-CoV-2 RBD), and collectrin domain of ACE2 fused to human IgG1 Fc fragment for increased stabilization and avidity, were designed (Glasgow et al., 2020). In silico, ACE2 variants Lys₂₆Arg and Thr₉₂Ile were predicted to have increased affinity for the viral S protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 Lys₂₆Arg and Thr₉₂Ile were more effective in blocking the entry of the SARS-CoV-2 S protein pseudotyped virus (Suryamohan et al., 2021). Another type of therapeutic molecules containging the hrsACE2 fused with a 5 kD albumin binding domain and bridged via a dimerization hinge-like peptide motif (termed ACE2 1-618-DDC-ABD) was first tested in an animal model prevented mortality in the treated group while untreated animals became severely hill and were found to have extensive pulmonary hemorrhage and mononuclear infiltrates (Hassler et al., 2021). The very rapid accumulation of three-dimensional structural data is likely to greatly accelerate the development of molecules aimed at treating COVID-19 patients (Sorokina et al., 2020).

Discussion

For virologists, ACE2 is the receptor for Sarbecoviruses. But to see ACE2 as a simple receptor necessary to initiate the replication cycle of the virus would be to ignore the essential role of ACE2 in the pathophysiology of COVID-19. ACE2 was not maintained during species evolution to wait for an unlikely meeting with a spike of Sarbecovirus. The regulatory function of the RAS pathway naturally devolved to ACE2 is the key element to be considered. The imbalance of the RAS pathway followed by the uncontrolled elevation of Ang II levels in SARS-CoV-2 infected patients and signaling through AT1R is the triggering event that can lead to severe forms of COVID-19. Thereby, COVID-19 is primarily a vascular rather than a respiratory disease and Ang II/AT1R blockade might attenuate progression to COVID-19.

The global COVID-19 Host Genetics Initiative (HGI) was set up to bring together international experts in human genetics and epidemiology to explore the genetic determinants of COVID-19 susceptibility, who have shed light on several host factors including ACE2, ACE, TMPRSS2, several chemokine receptors, the IL-6 receptor, IFN, and HLA, which are likely at the forefront of parameters affecting the disease severity (Correale et al., 2020; Ellinghaus et al., 2020; Initiative, 2020; Karaderi et al., 2020; Lorente et al., 2020; Nguyen et al., 2020; Strafella et al., 2020; Zhang Q. et al., 2020; Fricke-Galindo, 2021; Goujon et al., 2021; Martin-Sanchos et al., 2021; Pairo-Castineira et al., 2021). The list of genes possibly involved in the severity of COVID-19 continues to grow and indicates that the predisposition to severe COVID-19 is multifactorial. Understanding these pathways may help identifying targets for COVID-19 therapy and prophylaxis. Although the implication of a multiplicity of genes in the severity of COVID-19 is oubvious when considering the heterogenity in patient’s cases, we consider members of RAS as the main actors of the pathophysiological process. Besides ACE2 and Ang II, RAS can also be regulated by insertion/deletion (I/D) polymorphism of the ACE gene increasing the risk of severe forms of COVID-19 (Marshall et al., 2002; Harrap et al., 2003; Sayed-Tabatabaei et al., 2006; Gupta et al., 2009; Yamamoto et al., 2021). Association between the I/D polymorphism and blood pressure status has been reported (Jeunemaitre et al., 1992; Schmidt et al., 1993; Duru et al., 1994; Kario et al., 1999; Giner et al., 2000; Martinez et al., 2000; Agachan et al., 2003). Infusion of Ang I into normosensitive men was followed by higher venous levels of Ang II and increase in blood pressure in D/D carriers compared with I/I carriers (Ueda et al., 1995). Moreover, it has been reported that higher plasma IL-6 levels can be detected in ST segment elevation myocardial infarction patients, when the D allele is present (Dai et al., 2019). The possible association between the ACE genotype and the severity of COVID-19 should be further explored (Celik et al., 2021; Verma et al., 2021). One report indicates that the prevalence of D/D polymorphism is higher in COVID-19 patients with pulmonary embolism (PE) than patients without PE (Calabrese et al., 2021).

Our review highlights that the most important factors associated with severe COVID-19 outcome are related to the RAS and the regulation of blood pressure and coagulation. By focusing our attention to ACE2, we have come to the conclusion that this molecule may potentially play contrasting roles at different stages of the disease, with its ability to enable viral entry into the cell at early stages of infection thereby increasing disease susceptibility and later by decreasing Ang II/AT1R signaling thereby reducing the severity of the disease. Revisiting the structure and function of this molecule highlights the crucial role of ACE2 in the pathophysiology of sarbecoviruses-induced diseases, particularly in the context of inflammation and thrombosis. A low expression of ACE2 in the respiratory tract (e.g., epithelial cells, arterial and venous endothelial cells present in abundance in the lungs, and arterial smooth muscles) is associated with increased circulating levels of Ang II. The interaction of Ang II with AT1R and activation of various AT1R-dependent signaling pathways induce ROS release from monocytes able to trigger DNA damages and apoptosis in neighboring T-cells leading to lymphopenia, and endothelial injury by inhibiting NO synthesis. It is associated with vasoconstriction, hypertension, vascular permeability, fluid extravasation, and accelerated thrombosis in arterioles by activating hemostasis and the complement system. This process is accompanied by a recruitment of neutrophils and macrophages to the affected tissues leading to the “cytokine storm” (e.g., IL-6, MIP2, TNFα, and IFN responses). Perivascular inflammation is composed mainly of lymphocytes, with thrombi in the branches of the pulmonary artery and focal areas of congestion in the alveolar septal capillaries, as well as septal capillary lesions with wall and luminal fibrin deposition. Taken as a whole, these observations lead us to assume that instead of considering COVID-19 as respiratory tract diseases, we should rather see this disease as a clinical picture of hypercoagulopathy, microvascular immunothrombosis, and hyperinflammation. The loss of ACE2 function after the binding of SARS-CoV-2 is driven by mACE2 receptor endocytosis, activation of proteolytic cleavage of mACE2 and ACE2 gene transcriptional downregulation. Accurate quantification of RAS biomarkers should be added to the collection of tools aimed at monitoring COVID-19 infection both at pre-clinical and clinical levels.

According to the literature and our own observations, ACE2 and Ang II are the most relevant host factors in later stages of the disease and ACE2 should be seen as an ally in the global fight against COVID-19 and should be considered when designing appropriated drugs for COVID-19 therapy. It now appears that we can see the direction in wich work to deal with this disease should head. It requires treatment consisting in maintaining the homeostasis of the RAS pathway by preventing the elevation of the circulating levels of Ang II through sufficient biodisponibility of ACE2 to hydrolyze Ang II (including the use of human recombinant soluble ACE2), by inhibiting the Ang II/AT1R axis using ARBs which decrease the surface expression of AT1R, and/or by using calcium channel blokers as an alternative to ACEi and ARBS.

Funding

This work was supported by the French Government under the “Investissements d’avenir” (Investments for the Future) program managed by the Agence Nationale de la Recherche (French ANR: National Agency for Research; reference: Méditerranée Infection 10-IAHU-03 to Professor Didier Raoult), and annual funds from Aix-Marseille university and IRD to the MEPHI research unit (Director: Professor Jean-Christophe Lagier). Other funding sources were limited to the salaries of the authors (Center National de la Recherche Scientifique for CAD, Assistance Publique Hôpitaux de Marseille for LCJ), with no other role or involvement.

Publisher’s note

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References

• 1

  AbbasiJ. (2021). Choose ARBs over ACE inhibitors for first-line hypertension treatment, large new analysis suggests. JAMA326, 1244–1245. doi: 10.1001/jama.2021.14017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  AbdAllaS.LotherH.QuittererU. (2000). AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature407, 94–98. doi: 10.1038/35024095

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  AbdeenS.BdeirK.Abu-FanneR.MaragaE.HigaziM.KhurramN.et al. (2021). Alpha-defensins: risk factor for thrombosis in COVID-19 infection. Brit. J. Haematol.194, 44–52. doi: 10.1111/bjh.17503

  • CrossRef
  • Google Scholar

• 4

  Abu HasanZ.WilliamsH.IsmailN. M.OthmanH.CozierG. E.AcharyaK. R.et al. (2017). The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae. Sci. Rep.7:45409. doi: 10.1038/srep45409

  • CrossRef
  • Google Scholar

• 5

  AckermannM.VerledenS. E.KuehnelM.HaverichA.WelteT.LaengerF.et al. (2020). Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N. Engl. J. Med.383, 120–128. doi: 10.1056/NEJMoa2015432

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  AdvaniA.KellyD. J.CoxA. J.WhiteK. E.AdvaniS. L.ThaiK.et al. (2009). The (pro)renin receptor: site-specific and functional linkage to the vacuolar H+-ATPase in the kidney. Hypertension54, 261–269. doi: 10.1161/HYPERTENSIONAHA.109.128645

  • CrossRef
  • Google Scholar

• 7

  AfeltA.FrutosR.DevauxC. (2018). Bats, coronaviruses, and deforestation: toward the emergence of novel infectious diseases?Front. Microbiol.9:702. doi: 10.3389/fmicb.2018.00702

  • CrossRef
  • Google Scholar

• 8

  AfzaliB.NorisM.LambrechtB. N.KemperC. (2021). The state of complement in COVID-19. Nat. Rev. Immunol.22, 77–84. doi: 10.1038/s41577-021-00665-1

  • CrossRef
  • Google Scholar

• 9

  AgachanB.IsbirT.YilmazH.AkogluE. (2003). Angiotensin converting enzyme I/D, angiotensinogen T174M-M235T and angiotensin II type 1 receptor A1166C gene polymorphisms in Turkish hypertensive patients. Exp. Mol. Med.35, 545–549. doi: 10.1038/emm.2003.71

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  AguilarR.JedlickaA. E.MintzM.MahairakiV.ScottA. L.DimopoulosG. (2005). Global gene expression analysis of Anopheles gambiae responses to microbial challenge. Insect Biochem. Mol. Biol.35, 709–719. doi: 10.1016/j.ibmb.2005.02.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  AlbiniA.Di GuardoG.McClain NoonanD.LombardoM. (2020). The SARS-CoV-2 receptor, ACE-2, is expressed on many diferent cell types: implications for ACE-inhibitor-and angiotensin II receptor blocker-based cardiovascular therapies. Intern. Emerg. Med.15, 759–766. doi: 10.1007/s11739-020-02364-6

  • CrossRef
  • Google Scholar

• 12

  AldermanM. H.MadhavanS.OoiW. L.CohenH.SealeyJ. E.LaraghJ. H. (1991). Association of the renin sodium profile with the risk of myocardial-infarction in patients with hypertension. New Engl. J. Med.324, 1098–1104. doi: 10.1056/NEJM199104183241605

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  AlGhatrifM.TanakaT.MooreA. Z.BandinelliS.LakattaE. G.FerrucciL. (2021). Age-associated difference in circulating ACE2, the gateway for SARS-COV-2, in humans: results from the InCHIANTI study. GeroScience43, 619–627. doi: 10.1007/s11357-020-00314-w

  • CrossRef
  • Google Scholar

• 14

  AmorS.Fernandez BlancoL.BakerD. (2020). Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage. Clin. Exp. Immunol.202, 193–209. doi: 10.1111/cei.13523

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  AnderssonR.GebhardC.Miguel-EscaladaI.HoofI.BornholdtJ.BoydM.et al. (2014). An atlas of active enhancers across human cell types and tissues. Nature507, 455–461. doi: 10.1038/nature12787

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  AragaoD. S.CunhaT. S.AritaD. Y.AndradeM. C. C.FernandesA. B.WatanabeI. K. M.et al. (2011). Purification and characterization of angiotensin converting enzyme 2 (ACE2) from murine model of mesangial cell in culture. Int. J. Biol. Macromol.49, 79–84. doi: 10.1016/j.ijbiomac.2011.03.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  ArendseL. B.DanserA. H. J.PoglitschM.TouyzR. M.BurnettJ. C.Llorens-CortesC.et al. (2019). Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure. Pharmacol. Rev.71, 539–570. doi: 10.1124/pr.118.017129

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  AroorA.ZuberekM.DutaC.MeuthA.SowersJ. R.Whaley-ConnellA.et al. (2016). Angiotensin II stimulation of DPP4 activity regulates megalin in the proximal tubules. Int. J. Mol. Sci.17:780. doi: 10.3390/ijms17050780

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  ArthurJ. M.ForrestJ. C.BoehmeK. W.KennedyJ. L.OwensS.HerzogC.et al. (2021). Development of ACE2 autoantibodies after SARSCoV-2 infection. PLoS One16:e0257016. doi: 10.1371/journal.pone.025701

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  AvolioE.CarrabbaM.MilliganR.Kavanagh WilliamsonM.BeltramiA. P.GuptaK.et al. (2021). The SARS-CoV-2 spike protein disrupts human cardiac pericytes function through CD147-receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease. Clin. Sci.135, 2667–2689. doi: 10.1042/CS20210735

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  BaderM.AleninaN.YoungD.SantosR. A. S.TouyzR. M. (2018). The meaning of Mas. Hypertension72, 1072–1075. doi: 10.1161/HYPERTENSIONAHA.118.10918

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  BaggenJ.VanstreelsE.JansenS.DaelemansD. (2021). Cellular host factors for SARS-CoV-2 infection. Nat. Microbiol.6, 1219–1232. doi: 10.1038/s41564-021-00958-0

  • CrossRef
  • Google Scholar

• 23

  BaratchianM.McManusJ. M.BerkM. P.NakamuraF.MukhopadhyayS.XuW.et al. (2021). Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes. Sci. Rep.11:11130. doi: 10.1038/s41598-021-90491-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  BarkauskasC. E.CronceM. J.RackleyC. R.BowieE. J.KeeneD. R.StrippB. R.et al. (2013). Type 2 alveolar cells are stem cells in adult lung. J. Clin. Invest.123, 3025–3036. doi: 10.1172/JCI68782

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  BarkerH.ParkkilaS. (2020). Bioinformatic characterization of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2. PLoS One15:e0240647. doi: 10.1371/journal.pone.0240647

  • CrossRef
  • Google Scholar

• 26

  BastardP.RosenL. B.ZhangQ.MichailidisE.HoffmannH. H.ZhangY.et al. (2020). Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science370:eabd4585. doi: 10.1126/science.abd4585

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  BavishiC.MaddoxT. M.MesserliF. H. (2020). Coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers. JAMA Cardiol.5, 745–747. doi: 10.1001/jamacardio.2020.1282

  • CrossRef
  • Google Scholar

• 28

  BazzanM.MontaruliB.SciasciaS.CossedduD.NorbiatoC.RoccatelloD. (2020). Low ADAMTS 13 plasma levels are predictors of mortality in COVID-19 patients. Intern. Emerg. Med.15, 861–863. doi: 10.1007/s11739-020-02394-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  BeaconT. H.DelcuveG. P.DavieJ. R. (2021). Epigenetic regulation of ACE2, the receptor of the SARS-CoV-2 virus. Genome64, 386–399. doi: 10.1139/gen-2020-0124

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  BeanD. M.KraljevicZ.SearleT.BendayanR.KevinO.PicklesA.et al. (2020). Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust. Eur. J. Heart Fail.22, 967–974. doi: 10.1002/ejhf.1924

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  BenettiE.TitaR.SpigaO.CiolfiA.BiroloG.BrusellesA.et al. (2020). ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population. Eur. J. Hum. Genet.28, 1602–1614. doi: 10.1038/s41431-020-0691-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  BerkB. C.VekshteinV.GordonH. M.TsudaT. (1989). Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension13, 305–314. doi: 10.1161/01.HYP.13.4.305

  • CrossRef
  • Google Scholar

• 33

  BernardiS.ToffoliB.ZennaroC.TikellisC.MonticoneS.LosurdoP.et al. (2012). High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage. Nephrol. Dial. Transplant.27, 1793–1800. doi: 10.1093/ndt/gfr600

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  BerthelotJ. M.DrouetL.LiotéF. (2020). Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?Emerg. Microb. Infect.9, 1514–1522. doi: 10.1080/22221751.2020.1785336

  • CrossRef
  • Google Scholar

• 35

  BertinD.BrodovitchA.BezianeA.HugS.BouamriA.MegeJ. L.et al. (2020). Anticardiolipin IgG autoantibody level is an independent risk factor for COVID-19 severity. Arthritis Rheum.72, 1953–1955. doi: 10.1002/art.41409

  • CrossRef
  • Google Scholar

• 36

  BlumeC.JacksonC. L.SpallutoC. M.LegebekeJ.NazlamovaL.ConfortiF.et al. (2021). A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection. Nat. Genet.53, 205–214. doi: 10.1038/s41588-020-00759

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  BoklundA.HammerA. S.QuaadeM. L.RasmussenT. B.LohseL.StrandbygaardB.et al. (2021). SARS-CoV-2 in danish mink farms: course of the epidemic and a descriptive analysis of the outbreaks in 2020. Animals11:164. doi: 10.3390/ani11010164

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  BossoM.ThanarajT. A.Abu-FarhaM.AlanbaeiM.AbubakerJ.FahdA.-M. (2020). The two faces of ACE2: the role of ACE2 receptor and its polymorphisms in hypertension and COVID-19. Mol. Ther. Meth. Clin. Dev.18, 321–327. doi: 10.1016/j.omtm.2020.06.017

  • CrossRef
  • Google Scholar

• 39

  BoustanyC. M.BharadwajK.DaughertyA.BrownD. R.RandallD. C.CassisL. A. (2004). Activation of the systemic and adipose renin-angiotensin system in rats with diet-induced obesity and hypertension. Am. J. Physiol. Regul. Integrat. Comparat. Physiol.287, R943–R949. doi: 10.1152/ajpregu.00265.2004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  BrambillaM.GelosaP.RossettiL.CastiglioniL.ZaraC.CanzanoP.et al. (2018). Impact of angiotensin-converting enzyme inhibition on platelet tissue factor expression in stroke-prone rats. J. Hypertens.36, 1360–1371. doi: 10.1097/HJH.0000000000001702

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  BrestP.RefaeS.MograbiB.HofmanP.MilanoG. (2020). Host polymorphisms may impact SARS-CoV-2 infectivity. Trends Genet.36, 813–815. doi: 10.1016/j.tig.2020.08.003

  • CrossRef
  • Google Scholar

• 42

  BrewsterU. C.PerazellaM. A. (2004). The renin-angiotensinaldosterone system and the kidney disease. Am. J. Med.116, 263–272. doi: 10.1016/j.amjmed.2003.09.034

  • CrossRef
  • Google Scholar

• 43

  BrodardJ.Kremer HovingaJ. A.FontanaP.StudtJ. D.GruelY.GreinacherA. (2021). COVID-19 patients often show high-titer non-platelet-activating anti-PF4/heparin IgG antibodies. J. Thromb. Haemost.19, 1294–1298. doi: 10.1111/jth.15262

  • CrossRef
  • Google Scholar

• 44

  BrookeG. N.PrischiF. (2020). Structural and functional modelling of SARS-CoV-2 entry in animal models. Sci. Rep.10:15917. doi: 10.1038/s41598-020-72528-z

  • CrossRef
  • Google Scholar

• 45

  BrownN. J.VaughanD. E. (2000). Prothrombotic effects of angiotensin. Adv. Intern. Med.45, 419–429.

  • Google Scholar

• 46

  BurnhamS.SmithJ. A.LeeA. J.IsaacR. E.ShirrasA. D. (2005). The angiotensin-converting enzyme (ACE) gene family of Anopheles gambiae. BMC Genomics6:172. doi: 10.1186/1471-2164-6-172

  • CrossRef
  • Google Scholar

• 47

  Cabral-MarquesO.MarquesA.GiilL. M.De VitoR.RademacherJ.GuntherJ.et al. (2018). GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nat. Commun.9:5224. doi: 10.1038/s41467-018-07598-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  CaiH. (2020). Sex difference and smoking predisposition in patients with COVID-19. Lancet Respir. Med.8:e20. doi: 10.1016/S2213-2600(20)30117-X.P

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  Caillet-SaguyC.WolfN. (2021). PDZ-containing proteins targeted by the ACE2 receptor. Viruses13:2281. doi: 10.3390/v13112281

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  CalabreseC.AnnunziataA.CoppolaA.PafundiP. C.GuarinoS.Di SpiritoV.et al. (2021). ACE gene I/D polymorphism and acute pulmonary embolism in COVID19 pneumonia: a potential predisposing role. Front. Med.7:631148. doi: 10.3389/fmed.2020.631148

  • CrossRef
  • Google Scholar

• 51

  CalcagnileM.ForgezP.IannelliA.BucciC.AlifanoM.AlifanoP. (2021). Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 spike protein. Biochimie180, 143–148. doi: 10.1016/j.biochi.2020.11.004

  • CrossRef
  • Google Scholar

• 52

  CamargoS. M.SingerD.MakridesV.HuggelK.PosK. M.WagnerC. A.et al. (2009). Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. Gastroenterology136, 872–882.e3. doi: 10.1053/j.gastro.2008.10.055

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  CampbellC. M.KahwashR. (2020). Will complement inhibition be the new target in treating COVID-19 related systemic thrombosis?Circulation141, 1739–1741. doi: 10.1161/CIRCULATIONAHA.120.047419

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  Cantuti-CastelvetriL.OjhaR.PedroL. D.DjannatianM.FranzJ.KuivanenS.et al. (2020). Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science370, 856–860. doi: 10.1126/science.abd2985

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  CaoY.LiL.FengZ.WanS.HuangP.SunX.et al. (2020). Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov.6, 4–7. doi: 10.1038/s41421-020-0147-1

  • CrossRef
  • Google Scholar

• 56

  CardenasA.Rifas-ShimanS. L.SordilloJ. E.DeMeoD. L.BaccarelliA. A. (2021). DNA methylation architecture of the ACE2 gene in nasal cells of children. Sci. Rep.11:7107. doi: 10.1038/s41598-021-86494-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  Cardot-LecciaN.HubicheT.DellamonicaJ.Burel-VandenbosF. (2020). Pericyte alteration shed light on micro-vasculopathy in COVID-19 infection. Intensive Care Med.46, 1777–1778. doi: 10.1007/s00134-020-06147-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  CarsanaL.SanzagniA.NasrA.RossiR. S.PellegrinelliA.ZerbiP.et al. (2020). Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-Centre descriptive study. Lancet20, 1135–1140. doi: 10.1016/S1473-3099(20)30434-5

  • CrossRef
  • Google Scholar

• 59

  CarvelliJ.DemariaO.VélyF.BatistaL.Chouaki BenmansourN.FaresJ.et al. (2020). Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature588, 146–150. doi: 10.1038/s41586-020-2600-6

  • CrossRef
  • Google Scholar

• 60

  CelikS. K.GençG. C.PiskinN.AçikgözB.AltinsoyB.IssizB. K.et al. (2021). Polymorphisms of ACE (I/D) and ACE2 receptor gene (Rs2106809, Rs2285666) are not related to the clinical course of COVID-19: a case study. J. Med. Virol.93, 5947–5952. doi: 10.1002/jmv.27160

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  Cerdà-CostaN.Gomis-RüthF. X. (2014). Architecture and function of metallopeptidase catalytic domains. Protein Sci.23, 123–144. doi: 10.1002/pro.2400

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  ChappellM. C. (2019). The angiotensin-(1-7) Axis: formation and metabolism pathways. Springer nature Switzerland. Angiotensin22, 1–26. doi: 10.1007/978-3-030-22696-1_1

  • CrossRef
  • Google Scholar

• 63

  ChenJ.JiangQ.XiaX.LiuK.YuZ.TaoW.et al. (2020). Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell19:e13168. doi: 10.1111/acel.13168

  • CrossRef
  • Google Scholar

• 64

  ChenL.LiX.ChenM.FengY.XiongC. (2020). The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc. Res.116, 1097–1100. doi: 10.1093/cvr/cvaa078

  • CrossRef
  • Google Scholar

• 65

  ChenY. Y.LiuD.ZhangP.ZhongJ. C. (2016). Impact of ACE2 gene polymorphism on antihypertensive efficacy of ACE inhibitors. J. Hum. Hypertens.30, 766–771. doi: 10.1038/jhh.2016.24

  • CrossRef
  • Google Scholar

• 66

  ChenF.ZhangY.LiX.LiW.LiuX.XueX. (2021). The impact of ACE2 polymorphisms on COVID-19 disease: susceptibility, severity, and therapy. Front. Cell. Infect. Microbiol.11:753721. doi: 10.3389/fcimb.2021.753721

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  ChlamydasS.PapavassiliouA. G.PiperiC. (2020). Epigenetic mechanisms regulating COVID-19 infection. Epigenetics16, 263–270. doi: 10.1080/15592294.2020.1796896

  • CrossRef
  • Google Scholar

• 68

  ChungM. K.KarnikS.SaefJ.BergmannC.BarnardJ.LedermanM. M.et al. (2020). SARS-CoV-2 and ACE2: the biology and clinical data settling the ARB and ACEI controversy. EBioMed.58:102907. doi: 10.1016/j.ebiom.2020.102907

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  CiceriF.BerettaL.Mara ScandroglioA.ColomboS.LandoniG.RuggeriA.et al. (2020). Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis. Crit. Care Resusc.22, 95–97. doi: 10.51893/2020.2.pov2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  ClarkeN. E.BelyaevN. D.LambertD. W.TurnerA. J. (2014). Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress. Clin. Sci.126, 507–516. doi: 10.1042/CS20130291

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  Cohen-HaguenauerO.SoubrierF.Van CongN.SereroS.TurleauC.JegouC.et al. (1989). Regional mapping of the human renin gene to 1q32 by in situ hybridisation. Ann. Genet.32, 16–20.

  • Google Scholar

• 72

  Cole-JeffreyC. T.LiuM.KatovichM. J.RaizadaM. K.ShenoyV. (2015). ACE2 and microbiota: emerging targets for cardiopulmonary disease therapy. J. Cardiovasc. Pharmacol.66, 540–550. doi: 10.1097/FJC.0000000000000307

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  CorleyMJNdhlovuLC. DNA methylation analysis of the COVID-19 host cell receptor, angiotensin I converting enzyme 2 gene (ACE2) in the respiratory system reveal age and gender differences. (2020). Preprints [Preprint]. doi: 10.20944/preprints202003.0295.v1

  • CrossRef
  • Google Scholar

• 74

  CorrealeP.MuttiL.PentimalliF.BaglioG.SaladinoR. E.SileriP.et al. (2020). HLAB * 44 and C * 01 prevalence correlates with Covid19 spreading across Italy. Int. J. Mol. Sci.21:5205. doi: 10.3390/ijms21155205

  • CrossRef
  • Google Scholar

• 75

  CozziE.CalabreseF.SchiavonM.FeltraccoP.SevesoM.CarolloC.et al. (2017). Immediate and catastrophic antibody-mediated rejection in a lung transplant recipient with anti-angiotensin ii receptor type 1 and AntiEndothelin-1 receptor type a antibodies. Am. J. Transplant.17, 557–564. doi: 10.1111/ajt.14053

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  CrackowerM. A.SaraoR.OuditG. Y.YagilC.KozieradzkiI.ScangaS. E.et al. (2002). Angiotensinconverting enzyme 2 is an essential regulator of heart function. Nature417, 822–828. doi: 10.1038/nature00786

  • CrossRef
  • Google Scholar

• 77

  CrisanD.CarrJ. (2000). Angiotensin I-converting enzyme. J. Mol. Diagn.2, 105–115. doi: 10.1016/S1525-1578(10)60624-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  DahlbäckB.VilloutreixB. O. (2005). Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition Arterioscler. Thromb. Vasc. Biol.25, 1311–1320. doi: 10.1161/01.ATV.0000168421.13467.82

  • CrossRef
  • Google Scholar

• 79

  DaiS.DingM.LiangN.LiZ.GuanL.LiuH. (2019). Associations of ACE I/D polymorphism with the levels of ACE, kallikrein, angiotensin II and interleukin-6 in STEMI patients. Sci. Rep.9:19719. doi: 10.1038/s41598-019-56263-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  DaiC. F.XieX.MaY. T.YangY. N.LiX. M.FuZ. Y.et al. (2015). Relationship between CYP17A1 genetic polymorphism and essential hypertension in a Chinese population. Aging Dis.6, 486–498. doi: 10.14336/AD.2015.0505

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  DalyJ. L.SimonettiB.KleinK.ChenK. E.WilliamsonM. K.Anton-PlagaroC.et al. (2020). Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science370, 861–865. doi: 10.1126/science.abd3072

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  DamasJ.HughesG. M.KeoughK. C.PainterC. A.PerskyN. S.CorboM.et al. (2020). Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates. Proc. Natl. Acad. Sci. U. S. A.117, 22311–22322. doi: 10.1073/pnas.2010146117

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  DanilczykU.ErikssonU.CrackowerM. A.PenningerJ. M. (2003). A story of two ACEs. J. Mol. Med.81, 227–234. doi: 10.1007/s00109-003-0419-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  DarbaniB. (2020). The expression and polymorphism of entry machinery for COVID-19 in human: juxtaposing population groups, gender, and different tissues. Int. J. Environ. Res. Public Health17:3433. doi: 10.3390/ijerph17103433

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  DavietF.GuervillyC.BaldesiO.Bernard-GuervillyF.PilarczykE.GeninA.et al. (2020). Heparin-induced thromcytopenia in severe COVID-19. Circulation142, 1875–1877. doi: 10.1161/CIRCULATIONAHA.120.049015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  DavisJ. O.FreemanR. H. (1976). Mechanisms regulating renin release. Physiol. Rev.56, 1–56. doi: 10.1152/physrev.1976.56.1.1

  • CrossRef
  • Google Scholar

• 87

  de GasparoM.CattK. J.InagamiT.WrightJ. W.UngerT.International Union of Pharmacology. XXIII (2000). The angiotensin II receptors. Pharmacol. Rev.52, 415–472.

  • Google Scholar

• 88

  de KloetA. D.KrauseE. G.WoodsS. C. (2010). The renin angiotensin system and the metabolic syndrome. Physiol. Behav.100, 525–534. doi: 10.1016/j.physbeh.2010.03.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  DeloreyT. M.ZieglerC. G. K.HeimbergG.NormandR.YangY.SegerstolpeA.et al. (2021). COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature595, 107–113. doi: 10.1038/s41586-021-03570-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  DescampsG.VersetL.TrelcatA.HopkinsC.LechienJ. R.JourneF.et al. (2020). ACE2 protein landscape in the head and neck region: the conundrum of SARS-CoV-2 infection. Biology9:235. doi: 10.3390/biology9080235

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  DeshmukhV.MotwaniR.KumarA.KurnariC.RazaK. (2020). Histopathological observations in COVID-19: a systematic review. J. Clin. Pathol.74, 76–83. doi: 10.1136/jclinpath-2020-206995

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  DevauxC. A. (2020). Are ACE inhibitors and ARBs more beneficials than harmful in the treatment of severe COVID-19 disease?Cardiovasc. Med. Cardiol.7, 101–103. doi: 10.17352/2455-2976.000122

  • CrossRef
  • Google Scholar

• 93

  DevauxC. A.LagierJ.-C.RaoultD. (2021a). New insights into the physiopathology of COVID-19: SARS-CoV-2-associated gastrointestinal illness. Front. Med.8:640073. doi: 10.3389/fmed.2021.640073

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  DevauxC. A.PinaultL.DelerceJ.RaoultD.LevasseurA.FrutosR. (2021b). Spread of mink SARS-CoV-2 variants in humans: a model of Sarbecovirus interspecies evolution. Front. Microbiol.12:675528. doi: 10.3389/fmicb.2021.675528

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  DevauxC. A.PinaultL.OsmanI. O.RaoultD. (2021c). Can ACE2 receptor polymorphism predict species susceptibility to SARS-CoV-2?Front. Public Health8:608765. doi: 10.3389/fpubh.2020.608765

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  DevauxC. A.RaoultD. (2022). The impact of COVID-19 on populations living at high altitude: role of hypoxia-inducible factors (HIFs) signaling pathway in SARS-CoV-2 infection and replication. Front. Physiol.13:960308. doi: 10.3389/fphys.2022.960308

  • CrossRef
  • Google Scholar

• 97

  DevauxC. A.RolainJ. M.RaoultD. (2020). ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. J. Microbiol. Immnol. Inf.53, 425–435. doi: 10.1016/j.jmii.2020.04.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  Diez-FreireC.VazquezJ.Correa de AdjounianM. F.FerrariM. F. R.YuanL.SilverX.et al. (2006). ACE2 gene transfer attenuates hypertension-linked pathophysiological changes in the SHR. Physiol. Genomics27, 12–19. doi: 10.1152/physiolgenomics.00312.2005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  DikalovS. I.NazarewiczR. R. (2013). Angiotensin II-induced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease. Antioxid. Redox Signal.19, 1085–1094. doi: 10.1089/ars.2012.4604

  • CrossRef
  • Google Scholar

• 100

  DongB.YuQ. T.DaiH. Y.GaoY. Y.ZhouZ. L.ZhangL.et al. (2012). Angiotensin-converting enzyme-2 overexpression improves left ventricular remodeling and function in a rat model of diabetic cardiomyopathy. J. Am. Coll. Cardiol.59, 739–747. doi: 10.1016/j.jacc.2011.09.071

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  DongB.ZhangC.FengJ. B.ZhaoY. X.LiS. Y.YangY. P.et al. (2008). Overexpression of ACE2 enhances plaque stability in a rabbit model of atherosclerosis. Arteriosc. Thromb. Vascular Biol.28, 1270–1276. doi: 10.1161/ATVBAHA.108.164715

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  DonkorO. N.HenrikssonA.VasiljevicT.ShahN. P. (2007). Proteolytic activity of dairy lactic acid bacteria and probiotics as determinant of growth and in vitro angiotensin-converting enzyme inhibitory activity in fermented milk. Lait86, 21–38. doi: 10.1051/lait:2006023

  • CrossRef
  • Google Scholar

• 103

  DonoghueM.HsiehF.BaronasE. (2000). A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ. Res.87, E1–E9. doi: 10.1161/01.RES.87.5.e1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  DragunD.MullerD. N.BrasenJ. H.FritscheL.Nieminen-KelhaM.DechendR.et al. (2005). Angiotensin II type 1-receptor activating antibodies in renal allograft rejection. N. Engl. J. Med.352, 558–569. doi: 10.1056/NEJMoa035717

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  DuruK.FarrowS.WangJ. M.LocketteW.KurtzT. (1994). Frequency of a deletion polymorphism in the gene for angiotensin converting enzyme is increased in african-Americans with hypertension. Am. J. Hypertens.7, 759–762. doi: 10.1093/ajh/7.8.759

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  EllinghausD.DegenhardtF.BujandaL.ButiM.AlbillosA.InvernizziP.et al. (2020). Genomewide association study of severe Covid-19 with respiratory failure. N. Engl. J. Med.383, 1522–1534. doi: 10.1056/NEJMoa2020283

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  EpelmanS.ShresthaK.TroughtonR. W.FrancisG. S.SenS.KleinA. L.et al. (2009). Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes. J. Card. Fail.15, 565–571. doi: 10.1016/j.cardfail.2009.01.014

  • CrossRef
  • Google Scholar

• 108

  EpelmanS.TangW. H.ChenS. Y.LenteF. V.FrancisG. S.SenS.et al. (2008). Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. J. Am. Coll. Cardiol.52, 750–754. doi: 10.1016/j.jacc.2008.02.088

  • CrossRef
  • Google Scholar

• 109

  EscherR.BreakeyN.LammleB. (2020). Severe COVID-19 infection associated with endothelial activation. Thromb. Res.190:62. doi: 10.1016/j.thromres.2020.04.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  FaggianoP.BonelliA.ParisS.MilesiG.BisegnaS.BernardiN.et al. (2020). Acute pulmonary embolism in COVID-19 disease: preliminary report on seven patients. Int. J. Cardiol.313, 129–131. doi: 10.1016/j.ijcard.2020.04.028

  • CrossRef
  • Google Scholar

• 111

  FairweatherS. J.BroerA.O’MaraM. L.BroerS. (2012). Intestinal peptidases from functional complexes with neutral amino acid transporter B0AT1. Biochem. J.446, 135–148. doi: 10.1042/BJ20120307

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  FanC.LuW.LiK.DingY.WangJ. (2021). ACE2 expression in kidney and testis may cause kidney and testis infection in COVID-19 patients. Front. Med.7:563893. doi: 10.3389/fmed.2020.563893

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  FanR.MaoS. Q.GuT. L.ZhongF. D.GongM. L.HaoL. M.et al. (2017). Preliminary analysis of the association between methylation of the ACE2 promoter and essential hypertension. Mol. Med. Rep.15, 3905–3911. doi: 10.3892/mmr.2017.6460

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  FanZ.WuG.YueM.YeJ.ChenY.XuB.et al. (2019). Hypertension and hypertensive left ventricular hypertrophy are associated with ACE2 genetic polymorphism. Life Sci.225, 39–45. doi: 10.1016/j.lfs.2019.03.059

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  FanX.YbW.WangH.SunK.ZhangW.-l.SongX.et al. (2009). Polymorphisms of angiotensinconverting enzyme (ACE) and ACE2 are not associated with orthostatic blood pressure dysregulation in hypertensive patients. Acta Pharmacol. Sin.30, 1237–1244. doi: 10.1038/aps.2009.110

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  FangY.GaoF.LiuZ. (2019). Angiotensin-converting enzyme 2 attenuates inflammatory response and oxidative stress in hyperoxic lung injury by regulating NF-κB and Nrf2 pathways. QJM112, 914–924. doi: 10.1093/qjmed/hcz206

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  FangL.KarakiulakisR. M. (2020). Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?Lancet Respir. Med.8:e21. doi: 10.1016/S2213-2600(20)30116-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  FantiniJ.ChahinianH.YahiN. (2021). Leveraging coronavirus binding to gangliosides for innovative vaccine and therapeutic strategies against COVID-19. Biochem. Biophys. Res. Commun.538, 132–136. doi: 10.1016/j.bbrc.2020.10.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  FantiniJ.DevauxC. A.YahiN.FrutosR. (2022). The novel hamster-adapted SARS-CoV-2 Delta variant may be selectively advantaged in humans. J. Inf. Secur.84, e53–e54. doi: 10.1016/j.jinf.2022.03.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  FelmedenD. C.SpencerC. G. C.ChungN. A. Y.BelgoreF. M.BlannA. D.BeeversD. G.et al. (2003). Relation of thrombogenesis in systemic hypertension to angiogenesis and endothelial damage/dysfunction (a substudy of the Anglo-Scandinavian cardiac outcomes trial [ASCOT]). Am. J. Cardiol.92, 400–405. doi: 10.1016/s0002-9149(03)00657-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  FerrandA.NabhaniZ. A.TapiasN. S.MasE.HugoyJ. P.BarreauF. (2019). NOD2 expression in intestinal epithelial cells protects toward the development of inflammation and associated carcinogenesis. Cell. Mol. Gastroenterol. Hepatol.7, 357–369. doi: 10.1016/j.jcmgh.2018.10.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  FerrarioC. M.ChappellM. C.TallantE. A.BrosnihanK. B.DizD. I. (1997). Counterregulatory actions of angiotensin-(1-7). Hypertension30, 535–541. doi: 10.1161/01.hyp.30.3.535

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  FerrarioC. M.JessupJ.ChappellM. C.AverillD. B.BrosnihanK. B.TallantE. A.et al. (2005). Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation111, 2605–2610. doi: 10.1161/CIRCULATIONAHA.104.510461

  • CrossRef
  • Google Scholar

• 124

  FerrarioC. M.VaragicJ. (2010). The ANG-(1-7)/ACE2/mas axis in the regulation of nephron function. Am. J. Physiol. Ren. Physiol.298, F1297–F1305. doi: 10.1152/ajprenal.00110.2010

  • CrossRef
  • Google Scholar

• 125

  FerreiraA. J.ShenoyV.YamazatoY.SriramulaS.FrancisJ.YuanL.et al. (2009). Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. Am. J. Respir. Crit. Care Med.179, 1048–1054. doi: 10.1164/rccm.200811-1678OC

  • CrossRef
  • Google Scholar

• 126

  Fletcher-SandersjööA.BellanderB. M. (2020). Is COVID-19 associated thrombosis caused by overactivation of the complement cascade?Thromb. Res.194, 36–41. doi: 10.1016/j.thromres.2020.06.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  FogariR.ZoppiA.MugelliniA.MaffioliP.LazzariP.DerosaG. (2011). Role of angiotensin II in plasma PAI-1 changes induced by imidapril or candesartan in hypertensive patients with metabolic syndrome. Hypertens. Res.34, 1321–1326. doi: 10.1038/hr.2011.137

  • CrossRef
  • Google Scholar

• 128

  ForresterS. J.BoozG. W.SigmundC. D.CoffmanT. M.KawaiT.RizzoV.et al. (2018). Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology. Physiol. Rev.98, 1627–1738. doi: 10.1152/physrev.00038.2017

  • CrossRef
  • Google Scholar

• 129

  FournierD.LuftF. C.BaderM.GantenD.Andrade-NavarroM. A. (2012). Emergence and evolution of the renin–angiotensin–aldosterone system. J. Mol. Med.90, 495–508. doi: 10.1007/s00109-012-0894-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  Fraga-Silva RodrigoA.Costa-Fraga FabianaP.Murca TatianeM.Moraes PatrıciaL.Martins LimaA.Lautner RobertoQ.et al. (2013). Angiotensin-converting enzyme 2 activation improves endothelial function. Hypertension61, 1233–1238. doi: 10.1161/HYPERTENSIONAHA.111.00627

  • CrossRef
  • Google Scholar

• 131

  FrederichR. C.Jr.KahnB. B.PeachM. J.FlierJ. S. (1992). Tissue-specific nutritional regulation of angiotensinogen in adipose tissue. Hypertension19, 339–344. doi: 10.1161/01.hyp.19.4.339

  • CrossRef
  • Google Scholar

• 132

  Fricke-GalindoI. (2021). Falfa´ n-Valencia R genetics insight for COVID-19 susceptibility and severity: a review. Front. Immunol.12:622176. doi: 10.3389/fimmu.2021.622176

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  FrutosR.GavotteL.DevauxC. A. (2021). Understanding the origin of COVID-19 requires to change the paradigm on zoonotic emergence from the spillover to the circulation model. Infect. Genet. Evol.95:104812. doi: 10.1016/j.meegid.2021.104812

  • CrossRef
  • Google Scholar

• 134

  FrutosR.Serra-CoboJ.PinaultL.Lopez RoigM.DevauxC. A. (2021). Emergence of bat-related Betacoronaviruses: Hazard and risks. Front. Microbiol.12:591535. doi: 10.3389/fmicb.2021.591535

  • CrossRef
  • Google Scholar

• 135

  FrutosR.YahiN.GavotteL.FantiniJ.DevauxC. A. (2022). Role of spike compensatory mutations in the interspecies transmission of SARS-CoV-2. One Health15:100429. doi: 10.1016/j.onehlt.2022.100429

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  FuglsangA.RattrayF. P.NilssonD.NyborgN. C. B. (2003). Lactic acid bacteria: inhibition of angiotensin converting enzyme in vitro and in vivo. Antonie Van Leeuwenhoek83, 27–34. doi: 10.1023/A:1022993905778

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  FunakoshiY.IchikiT.TakedaK.TokunoT.LinoN.TakeshitaA. (2002). Critical role of cAMP-response element-binding protein for angiotensin II-induced hypertrophy of vascular smooth muscle cells. J. Biol. Chem.277, 18710–18717. doi: 10.1074/jbc.M110430200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  FuruhashiM.MoniwaN.MitaT.FuseyaT.IshimuraS.OhnoK.et al. (2015). Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am. J. Hypertens.28, 15–21. doi: 10.1093/ajh/hpu086

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  FuruhashiM.MoniwaN.TakizawaH.UraN.ShimamotoK. (2020). Potential differential effects of renin-angiotensin system inhibitors on SARS-CoV-2 infection and lung injury in COVID-19. Hypertens. Res.43, 837–840. doi: 10.1038/s41440-020-0478-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  GáborikZ.SzaszákM.SzidonyaL.BallaB.PakuS.CattK. J.et al. (2001). Beta-arrestin-and dynamin-dependent endocytosis of the AT1 angiotensin receptor. Mol. Pharmacol.59, 239–247. doi: 10.1124/mol.59.2.239

  • CrossRef
  • Google Scholar

• 141

  GagiannisD.SteinestelJ.HackenbrochC.SchreinerB.HannemannM.BlochW.et al. (2020). Clinical, serological, and histopathological similarities between severe COVID-19 and acute exacerbation of connective tissue disease-associated interstitial lung disease (CTD-ILD). Front. Immunol.11:587517. doi: 10.3389/fimmu.2020.587517

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  GaidarovI.AdamsJ.FrazerJ.AnthonyT.ChenX.GatlinJ.et al. (2018). Angiotensin (1-7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor. Cell. Signal.50, 9–24. doi: 10.1016/j.cellsig.2018.06.007

  • CrossRef
  • Google Scholar

• 143

  GallucioM.PantanellaM.GludiceD.BresciaS.IndiveriC. (2020). Low temperature bacterial expression of the neutral amino acid transporters SLC1A5 (ASCT2), and SLC6A19 (B0AT1). Mol. Biol. Rep.47, 7283–7289. doi: 10.1007/s11033-020-05717-8

  • CrossRef
  • Google Scholar

• 144

  GandoS.WadaT. (2021). Thromboplasminflammation in COVID-19 coagulopathy: three viewpoints for diagnostic and therapeutic strategies. Front. Immunol.12:649122. doi: 10.3389/fimmu.2021.649122

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  GaoS.ZhangL. (2020). ACE2 partially dictates the host range and tropism of SARS-CoV-2. Comput. Struct. Biotechnol. J.18, 4040–4047. doi: 10.1016/j.csbj.2020.11.032

  • CrossRef
  • Google Scholar

• 146

  Garcia-EscobarA.Jimenez-ValeroS.GaleoteG.Jurado-RomanA.Garcia-RodriguezJ.MorenoR. (2021). The soluble catalytic ectodomain of ACE2 a biomarker of cardiac remodelling: new insights for heart failure and COVID19. Heart Fail. Rev.26, 961–971. doi: 10.1007/s10741-020-10066-6

  • CrossRef
  • Google Scholar

• 147

  GarridoA. M.GriendlingK. K. (2009). NADPH oxidases and angiotensin II receptor signaling. Mol. Cell. Endocrinol.302, 148–158. doi: 10.1016/j.mce.2008.11.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  GarvinM. R.AlvarezC.MillerJ. I.PratesE. T.WalkerA. M.AmosB. K.et al. (2020). A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. elife9:e59177. doi: 10.7554/eLife.59177

  • CrossRef
  • Google Scholar

• 149

  GayL.MelenotteC.LakbarI.MezouarS.DevauxC.RaoultD.et al. (2021). Sexual dimorphism and gender in infectious diseases. Front. Immunol.12:698121. doi: 10.3389/fimmu.2021.698121

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  GeX. Y.LiJ. L.YangX. L.ChmuraA. A.ZhuG.EpsteinJ. H.et al. (2013). Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature503, 535–538. doi: 10.1038/nature12711

  • CrossRef
  • Google Scholar

• 151

  GerardL.LecocqM.BouzinC.HotonD.SchmitG.PereiraJ. P.et al. (2021). Increased angiotensin-converting enzyme 2 and loss of alveolar type II cells in COVID-19 related ARDS. Am. J. Respir. Crit. Care Med.204, 1024–1034. doi: 10.1164/rccm.202012-4461OC

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  GhatageT.Gopal GoyalS.DharA.BhatA. (2021). Novel therapeutics for the treatment of hypertension and its associated complications: peptide-and nonpeptide-based strategies. Hypertens. Res.44, 740–755. doi: 10.1038/s41440-021-00643-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  GheblawiM.WangK.ViveirosA.NguyenQ.ZhongJ. C.TurnerA. J.et al. (2020). Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ. Res.126, 1456–1474. doi: 10.1161/CIRCRESAHA.120.317015

  • CrossRef
  • Google Scholar

• 154

  GinerV.PochE.BragulatE.OriolaJ.GonzalezD.CocaA.et al. (2000). Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential hypertension. Hypertension35, 512–517. doi: 10.1161/01.hyp.35.1.512

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  GjymishkaA.KuleminaL. V.ShenoyV.KatovichM. J.OstrovD. A.RaizadaM. K. (2010). Diminazene aceturate is an ACE2 activator and a novel antihypertensive drug. FASEB J.24:1032. doi: 10.1096/fasebj.24.1_supplement.1032.3

  • CrossRef
  • Google Scholar

• 156

  GlasgowA.GlasgowJ.LimontaD.SolomonP.LuiI.ZhangY.et al. (2020). Engineered ACE2 receptor traps potently neutralize SARS-CoV-2. Proc. Natl. Acad. Sci. U. S. A.117, 28046–28055. doi: 10.1073/pnas.2016093117

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  GoldblattH.LynchJ.HanzalR. F.SummervilleW. W. (1934). Studies on experimental hypertension: I. the production of persistent elevation of systolic blood pressure by means of renal ischemia. J. Exp. Med.59, 347–379. doi: 10.1084/jem.59.3.347

  • CrossRef
  • Google Scholar

• 158

  GómezJ.AlbaicetaG. M.García-ClementeM.López-LarreaC.Amado RodríguezL.Lopez-AlonsoI.et al. (2020). Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene762:145102. doi: 10.1016/j.gene.2020.145102

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  GonzalezA. A.LaraL. S.PrietoM. C. (2017). Role of collecting duct renin in the pathogenesis of hypertension. Curr. Hypertens. Rep.19:62. doi: 10.1007/s11906-017-0763-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  GoruS. K.KadakolA.MalekV.PandeyA.GaikwadS. N. A. B. (2017). Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT(2) receptor expression in a rat model of type1 diabetes. Br. J. Pharmacol.174, 3118–3130. doi: 10.1111/bph.13946

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  GoshuaG.PineA. B.MeizlishM. L.ChangC. H.ZhangH.BahelP.et al. (2020). Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-Centre, cross-sectional study. Lancet Heamatol.7, e575–e582. doi: 10.1016/S2352-3026(20)30216-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  GoujonCRebendenneARoyPBonaventureBValadaoACDesmaretsLet al. (2021). Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs. Research Square [Preprint]. doi: 10.21203/rs.3.rs-555275/v1

  • CrossRef
  • Google Scholar

• 163

  GoulterA. B.GoddardM. J.AllenJ. C.ClarkK. L. (2004). ACE2 gene expression is up-regulated in the human failing heart. BMC Med.2:19. doi: 10.1186/1741-7015-2-19

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  GrahamR. L.DonaldsonE. F.BaricR. S. (2013). A decade after SARS: strategies to control emerging coronaviruses. Nat. Rev. Microbiol.11, 836–848. doi: 10.1038/nrmicro3143

  • CrossRef
  • Google Scholar

• 165

  GreenbergB. (2008). An ACE in the hole alternative pathways of the renin angiotensin system and their potential role in cardiac remodeling. J. Am. Coll. Cardiol.52, 755–757. doi: 10.1016/j.jacc.2008.04.059

  • CrossRef
  • Google Scholar

• 166

  GriendlingK. K.Ushio-FukaiM.LassègueB.AlexanderR. W. (1997). Angiotensin II signaling in vascular smooth muscle. Hypertension29, 366–370. doi: 10.1161/01.HYP.29.1.366

  • CrossRef
  • Google Scholar

• 167

  GuH.XieZ.LiT.ZhangS.LaiC.ZhuP.et al. (2016). Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci. Rep.6:19840. doi: 10.1038/srep19840

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  GuignabertC.de ManF.LombesM. (2018). ACE2 as therapy for pulmonary arterial hypertension: the good outweighs the bad. Eur. Respir. J.51:1800848. doi: 10.1183/13993003.00848-2018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  GuoL.RenL.YangS.XiaoM.ChangD.YangF.et al. (2020). Profiling early humoral response to diagnose novel coronavirus disease (COVID-19). Clin. Infect. Dis.71, 778–785. doi: 10.1093/cid/ciaa310

  • CrossRef
  • Google Scholar

• 170

  GuptaS.AqrawalB. K.GoelR. K.SehajpalP. K. (2009). Angiotensin-converting enzyme gene polymorphism in hypertensive rural population of Haryana, India. J. Emerg. Trauma Shock.2, 150–154. doi: 10.4103/0974-2700.55323

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  GurleyS. B.Riquier-BrisonA. D. M.SchnermannJ.SparksM. A.AllenA. M.HaaseV. H.et al. (2011). AT1A angiotensin receptors in the renal proximal tubule regulate blood pressure. Cell Metab.13, 469–475. doi: 10.1016/j.cmet.2011.03.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  GustafssonF.Holstein-RathlouN. H. (1999). Angiotensin II modulates conducted vasoconstriction to norepinephrine and local electrical stimulation in rat mesenteric arterioles. Cardiovasc. Res.44, 176–184. doi: 10.1016/S0008-6363(99)00174-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  HaberP. K.YeM.WysockiJ.MaierC.HaqueS. K.BattleD. (2014). Angiotensin-converting enzyme 2–independent action of presumed angiotensin-converting enzyme 2 activators. Hypertension63, 774–782. doi: 10.1161/HYPERTENSIONAHA.113.02856

  • CrossRef
  • Google Scholar

• 174

  HadmanJ. A.MortY. J.CatanzaroD. F.TallamJ. T.BaxterJ. D.MorrisB. J.et al. (1984). Primary structure of human renin gene. DNA3, 457–468. doi: 10.1089/dna.1.1984.3.457

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  HammingI.TimensW.BulthuisM.LelyT.NavisG.van GoorH. (2004). Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. J. Pathol.203, 631–637. doi: 10.1002/path.1570

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  HanH.MaQ.LiC.LiuR.ZhaoL.WangW.et al. (2020). Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg. Microb. Infect.9, 1123–1130. doi: 10.1080/22221751.2020.1770129

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  HanY.RungeM. S.BrasierA. R. (1999). Angiotensin II induces Interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kB transcription factors. Circ. Res.84, 695–703. doi: 10.1161/01.RES.84.6.695

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  HarrapS. B.TzourioC.CambienF.PoirierO.RaouxS.ChalmersJ.et al. (2003). The ACE gene I/D polymorphism is not associated with the blood pressure and cardiovascular benefits of ACE inhibition. Hypertension42, 297–303. doi: 10.1161/01.HYP.0000088322.85804.96

  • CrossRef
  • Google Scholar

• 179

  HarzallahI.DebliquisA.DrenouB. (2020). Lupus anticoagulant is frequent in patients with Covid-19. J. Thromb. Haemost.18, 2064–2065. doi: 10.1111/jth.14867

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  HaschkeM.SchusterM.PoglitschM.LoinerH.SalzbergM.BruggisserM.et al. (2013). Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin. Pharmacokinet.52, 783–792. doi: 10.1007/s40262-013-0072-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  HashimotoT.PerlotT.RehmanA.TrichereauJ.IshiguroH.PaolinoM.et al. (2012). ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature487, 477–481. doi: 10.1038/nature11228

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  HasslerLWysockiJGelardenITomatsidouAGulaHNicoleascuVet al. (2021). A novel soluble ACE2 protein totally protects from lethal disease caused by SARS-CoV-2 infection. bioRxiv [Preprint] doi: 10.1101/2021.03.12.435191

  • CrossRef
  • Google Scholar

• 183

  HeM.HeX.XieQ.ChenF.HeS. (2006). Angiotensin II induces the expression of tissue factor and its mechanism in human monocytes. Thromb. Res.117, 579–590. doi: 10.1016/j.thromres.2005.04.033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  HeenemanS.HaendelerJ.SaitoY.IshidaM.BerkB. C. (2000). Angiotensin II induces transactivation of two different populations of the platelet-derived growth factor beta receptor. Key role for the p66 adaptor protein Shc. J. Biol. Chem.275, 15926–15932. doi: 10.1074/jbc.M909616199

  • CrossRef
  • Google Scholar

• 185

  HelmsJ.TacquardC.SeveracF.Leonard-LorantI.OhanaM.DelabrancheX.et al. (2020). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med.46, 1089–1098. doi: 10.1007/s00134-020-06062-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  HemnesA. R.RathinasabapathyA.AustinE. A.BrittainE. L.CarrierE. J.ChenX.et al. (2018). A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur. Respir. J.51:1702638. doi: 10.1183/13993003.02638-2017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  HendrenN. S.DraznerM. H.BozkurtB.CooperL. T. (2020). Description and proposed management of the acute COVID-19 cardiovascular syndrome. Circulation141, 1903–1914. doi: 10.1161/CIRCULATIONAHA.120.047349

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  HenzingerH.BarthD. A.KlecC.PichlerM. (2020). Non-Coding RNAs and SARS-related coronaviruses. Viruses12:1374. doi: 10.3390/v12121374

  • CrossRef
  • Google Scholar

• 189

  Hernández PradaJ. A.FerreiraA. J.KatovichM. J.ShenoyV.QiY.SantosR. A.et al. (2008). Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension51, 1312–1317. doi: 10.1161/HYPERTENSIONAHA.107.108944

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  HeurichA.Hofmann-WinklerH.GiererS.LiepoldT.JahnO.PöhlmannS. (2014). TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J. Virol.88, 1293–1307. doi: 10.1128/JVI.02202-13

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  HeymanS. N.KinanehS.AbassiZ. (2021). The duplicitous nature of ACE2 in COVID-19 disease. EBioMed.67:103356. doi: 10.1016/j.ebiom.2021.103356

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  HikmetF.MéarL.EdvinssonA.MickeP.UhlénM.LindskogC. (2020). The protein expression profile of ACE2 in human tissues. Mol. Syst. Biol.16:e9610. doi: 10.15252/msb.20209610

  • CrossRef
  • Google Scholar

• 193

  HiranoT.MurakamiM. (2020). COVID-19: a new virus, but a familiar receptor and cytokine release syndrome. Immunity52, 731–733. doi: 10.1016/j.immuni.2020.04.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  HoffmannM.Kleine-WeberH.SchroederS.KrugerN.HerrlerT.ErichsenS.et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cells181, 271–280.e8. doi: 10.1016/j.cell.2020.02.052

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  HofmanP.CopinM. C.Tauziede-EspariatA.Adle-BiassetteH.FortarezzaF.PasseronT.et al. (2021). Histopathological features due to the SARS-CoV-2 [in French]. Ann. Pathol.41, 9–22. doi: 10.1016/j.annpat.2020.12.009

  • CrossRef
  • Google Scholar

• 196

  HofmannH.PyrcK.van der HoekL.GeierM.BerkhoutB.PöhlmannS. (2005). Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc. Natl. Acad. Sci. U. S. A.102, 7988–7993. doi: 10.1073/pnas.0409465102

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  HorowitzJEKosmickiJADamaskASharmaDRobertsGHLJusticeAEet al. Genome-wide analysis in 756, 646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease [Internet]. medRxiv [Preprint]. (2021). doi: 10.1101/2020.12.14.20248176

  • CrossRef
  • Google Scholar

• 198

  HouY.ZhaoJ.MartinW.KallianpurA.ChungM. K.JehiL.et al. (2020). New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Med.18:216. doi: 10.1186/s12916-020-01673-z

  • CrossRef
  • Google Scholar

• 199

  HuangC.WangY.LiX.RenL.ZhaoJ.HuY.et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet395, 497–506. doi: 10.1016/S0140-6736(20)30183-5

  • CrossRef
  • Google Scholar

• 200

  HubertC.HouotA. M.CorvolP.SoubrierF. (1991). Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J. Biol. Chem.266, 15377–15383. doi: 10.1016/S0021-9258(18)98626-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  IchiharaA.YatabeM. S. (2019). The (pro)renin receptor in health and disease. Nat. Rev. Nephrol.15, 693–712. doi: 10.1038/s41581-019-0160-5

  • CrossRef
  • Google Scholar

• 202

  ImaiY.KubK.RaoS.HuanY.GuoF.GuanB.et al. (2005). Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature436, 112–116. doi: 10.1038/nature03712

  • CrossRef
  • Google Scholar

• 203

  InitiativeC.-H. G. (2020). The COVID-19 host genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARSCoV-2 virus pandemic. Eur. J. Hum. Genet.28, 715–718. doi: 10.1038/s41431-020-0636-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204

  IssaH.EidA. H.BerryB.TakhvijiV.KhosraviA.MantashS.et al. (2021). Combination of angiotensin (1-7) agonists and convalescent plasma as a new strategy to overcome angiotensin converting enzyme 2 (ACE2) inhibition for the treatment of COVID-19. Front. Med.8:620990. doi: 10.3389/fmed.2021.620990

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  ItoyamaS.KeichoN.HijikataM.QuyT.Chi PhiN.LongH. T.et al. (2005). Identifcation of an alternative 5’-untranslated exon and new polymorphisms of angiotensin-converting enzyme 2 gene: lack of association with SARS in the Vietnamese population. Am. J. Med. Genet.136, 52–57. doi: 10.1002/ajmg.a.30779

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  JackmanH. L.MassadM. G.SekosanM.TanF.BrovkovychV.MarcicB. M.et al. (2002). Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin a. Hypertension39, 976–981. doi: 10.1161/01.HYP.0000017283.67962.02

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  JacobyD. S.RaderD. J. (2003). Renin-angiotensin system and atherothrombotic disease: from genes to treatment. Arch. Intern. Med.163, 1155–1164. doi: 10.1001/archinte.163.10.1155

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  JamesM. N.SieleckiA. R. (1985). Stereochemical analysis of peptide bond hydrolysis catalyzed by the aspartic proteinase penicillopepsin. Biochemistry24, 3701–3713. doi: 10.1021/bi00335a045

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  JaspardE.WeiI.Alhenc-GelasF. (1993). Differences in the properties and enzymatic specifities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides. J. Biol. Chem.268, 9496–9503. doi: 10.1016/S0021-9258(18)98378-X

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  JehpssonL.SunJ.NilssonP. M.EdsfeldtA.SwärdP. (2021). Serum renin levels increase with age in boys resulting in higher renin levels in Young men compared to Young women, and soluble angiotensin-converting enzyme 2 correlates with renin and body mass index. Front. Physiol.11:622179. doi: 10.3389/fphys.2020.622179

  • CrossRef
  • Google Scholar

• 211

  JeunemaitreX.LiftonR. P.HuntS. C.WilliamsR. R.LalouelJ. M. (1992). Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension. Nat. Genet.1, 72–75. doi: 10.1038/ng0492-72

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  JiaH. P.LookD. C.TanP. (2009). Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia. Am. J. Phys. Lung Cell. Mol. Phys.297, L84–L96. doi: 10.1152/ajplung.00071.2009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  JinY.JiW.YangH.ChenS.ZhangW.DuanG. (2020). Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches. Signal Transduct. Target. Ther.5:293. doi: 10.1038/s41392-020-00454-7

  • CrossRef
  • Google Scholar

• 214

  JohnsonJ. A.WestJ.MaynardK. B.HemnesA. R. (2011). ACE2 improves right ventricular function in a pressure overload model. PLoS One6:e20828. doi: 10.1371/journal.pone.0020828

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  KaiH.KaiM.NiiyamaH.OkinaN.SasakiM.MaedaT.et al. (2021). Overexpression of angiotensin-converting enzyme 2 by renin-angiotensin system inhibitors. Truth or myth? A systematic review of animal studies. Hypertens. Res.44, 955–968. doi: 10.1038/s41440-021-00641-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  KaraderiT.BarekeH.KunterI.SeytanogluA.CagnanI.BalciD.et al. (2020). Host genetics at the intersection of autoimmunity and COVID-19: a potential key for heterogeneous COVID-19 severity. Front. Immunol.11:586111. doi: 10.3389/fimmu.2020.586111

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  KarioK.HoshideS.UmedaY.SatoY.IkedaU.NishiumaS.et al. (1999). Angiotensinogen and angiotensin-converting enzyme genotypes, and day and night blood pressures in elderly Japanese hypertensives. Hypertens. Res.22, 95–103. doi: 10.1291/hypres.22.95

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  KarnikS. S.SinghK. D.TirupulaK.UnalH. (2017). Significance of angiotensin 1-7 coupling with MAS1 receptor and other GPGRs to the renin-angiotensin system: IUPHAR review 22. Br. J. Pharmacol.174, 737–753. doi: 10.1111/bph.13742

  • CrossRef
  • Google Scholar

• 219

  KassanM.Ait-AissaK.RadwanE.MaliV.HaddoxS.GabaniM.et al. (2016). Essential role of smooth muscle STIM1 in hypertension and cardiovascular dysfunction. Arterioscler. Thromb. Vasc. Biol.36, 1900–1909. doi: 10.1161/ATVBAHA.116.307869

  • CrossRef
  • Google Scholar

• 220

  KassanM.GalánM.PartykaM.SaifudeenZ.HenrionD.TrebakM.et al. (2012). Endoplasmic reticulum stress is involved in cardiac damage and vascular endothelial dysfunction in hypertensive mice. Arterioscler. Thromb. Vasc. Biol.32, 1652–1661. doi: 10.1161/ATVBAHA.112.249318

  • CrossRef
  • Google Scholar

• 221

  KatsoularisI.Fonseca-RodriguezO.FarringtonP.JerndalH.Häggström LundevallerE.SundM.et al. (2022). Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study. BMJ377:e069590. doi: 10.1136/bmj-2021-069590

  • CrossRef
  • Google Scholar

• 222

  KellamP.BarclayW. (2020). The dynamics of humoral immune responses following SARS-CoV-2 infection and the potential for reinfection. J. Gen. Virol.101, 791–797. doi: 10.1099/jgv.0.001439

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  Khaddaj-MallatR.AldibN.BernardM.PaquetteA. S.FerreiraA.LecordierS.et al. (2021). SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via spike protein. Neurobiol. Dis.161:105561. doi: 10.1016/j.nbd.2021.105561

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  KhanA.BenthinC.ZenoB.AlbertsonT. E.BoydJ.ChristieJ. D.et al. (2017). A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit. Care21:234. doi: 10.1186/s13054-017-1823-x

  • CrossRef
  • Google Scholar

• 225

  KhayatASde AssumpcPPMeireles KhayatBCThomaz Arau JoTMBatista-GomesJAImbiribaL.C.et al. (2020). ACE2 polymorphisms as potential players in COVID-19 outcome. PLoS One15:e0243887. doi: 10.1371/journal.pone.024388

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  KintscherU.SlagmanA.DomenigO.RöhleR.KonietschkeF.PoglitschM.et al. (2020). Plasma angiotensin peptide profiling and ACE (angiotensin-converting enzyme)-2 activity in COVID-19 patients treated with pharmacological blockers of the renin-angiotensin system. Hypertension76, e34–e36. doi: 10.1161/HYPERTENSIONAHA.120.15841

  • CrossRef
  • Google Scholar

• 227

  KlicheJ.KussH.AliM.IvarssonY. (2021). Cytoplasmic short linear motifs in ACE2 and integrin B3 link SARS-CoV-2 host cell receptors to mediators of endocytosis and autophagy. Sci. Signal.14:ebaf1117. doi: 10.1126/scisignal.abf1117

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  KokK. H.WongS. C.ChanW. M.LeiW.ChuA. W. H.IpJ. D.et al. (2022). Cocirculation of two SARSCoV-2 variant strains within imported pet hamsters in Hong Kong. Emerg. Microb. Infect.11, 689–698. doi: 10.1080/22221751.2022.2040922

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  KokaV.HuangX. R.ChungA. C. K.WangW.TruongL. D.LanH. Y. (2008). Angiotensin II up-regulates angiotensin I converting enzyme (ACE), but Down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am. J. Pathol.172, 1174–1183. doi: 10.2353/ajpath.2008.070762

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  KougiasP.ChaiH.LinP. H.YaoQ.LumsdenA. B.ChenC. (2005). Defensins and cathelicidins: neutrophil peptides with roles in inflammation, hyperlipidemia and atherosclerosis. J. Cell. Mol. Med.9, 3–10. doi: 10.1111/j.1582-4934.2005.tb00332.x

  • CrossRef
  • Google Scholar

• 231

  KragstrupT. W.Sogaard SinghH.GrundbergI.Langkilde-Lauesen NielsenA.RivelleseF.MehtaA.et al. (2021). Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients. PLoS One16:e0252799. doi: 10.1371/journal.pone.0252799

  • CrossRef
  • Google Scholar

• 232

  KrishnamurthyS.LockeyR. F.KolliputiN. (2021). Soluble ACE2 as a potential therapy for COVID-19. Am. J. Phys. Cell Physiol.320, C279–C281. doi: 10.1152/ajpcell.00478.2020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  KsiazekT. G.ErdmanD.GoldsmithC. S.ZakiS. R.PeretT.EmeryS.et al. (2003). A novel coronavirus associated with severe acute respiratory syndrome. N. Engl. J. Med.348, 1953–1966. doi: 10.1056/NEJMoa030781

  • CrossRef
  • Google Scholar

• 234

  KuanT. C.YangT. H.WenC. H.ChenM. Y.LeeI. L.LinC. S. (2011). Identifying the regulatory element for human angiotensin-converting enzyme 2 (ACE2) expression in human cardiofibroblasts. Peptides32, 1832–1839. doi: 10.1016/j.peptides.2011.08.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  KubaK.ImaiY.RaoS.GaoH.GuoF.GuanB.et al. (2005). A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med.11, 875–879. doi: 10.1038/nm1267

  • CrossRef
  • Google Scholar

• 236

  KuleminaL. V.OstrovD. A. (2011). Prediction of off-target effects on angiotensin-converting enzyme 2. J. Biomol. Screen.16, 878–885. doi: 10.1177/1087057111413919

  • CrossRef
  • Google Scholar

• 237

  KunduraL.GimenezS.CezarR.AndréS.YounasM.LinY. L.et al. (2022). Angiotensin II induces reactive oxygen species, DNA damage, and T-cell apoptosis in severe COVID-19. J. Allergy Clin. Immunol.150, 594–603.e2. doi: 10.1016/j.jaci.2022.06.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  KwakernaakA. J.RoksnoerL. C.Lambers HeerspinkH. J.Ven den Berg-GarreldsI.LochornG. A.EmbdenJ. H.et al. (2017). Effects of direct renin blockade on renal & systemic hemodynamics and on RAAS activity, in weight excess and hypertension: a randomized clinical trial. PLoS One12:e0169258. doi: 10.1371/journal.pone.0169258

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  LamS. D.BordinN.WamanV. P.ScholesH. M.AshfordP.SenN.et al. (2020). SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals. Sci. Rep.10:16471. doi: 10.1038/s41598-020-71936-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  LambertD. W.ClarkeN. E.HooperN. M.TurnerA. J. (2008). Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain. FEBS Lett.582, 385–390. doi: 10.1016/j.febslet.2007.11.085

  • CrossRef
  • Google Scholar

• 241

  LambertD. W.YarskiM.WarnerF. J. (2005). Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J. Biol. Chem.280, 30113–33019. doi: 10.1074/jbc.M505111200

  • CrossRef
  • Google Scholar

• 242

  LamersM. M.BeumerJ.van der VaartJ.KnoopsK.PuschhofJ.BreugemT. I.et al. (2020). SARS-CoV-2 productively infects human gut enterocytes. Science369, 50–54. doi: 10.1126/science.abc1669

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 243

  LanJ.GeJ.YuJ.ShanS.ZhouH.FanS.et al. (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature581, 215–220. doi: 10.1038/s41586-020-2180-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  LanjanianH.Moazzam-JaziM.HedayatiM.AkbarzadehM.GuityK.Sedaghati-KhayatB.et al. (2021). SARS-CoV-2 infection susceptibility infuenced by ACE2 genetic polymorphisms: insights from Tehran cardio-metabolic genetic study. Sci. Rep.11:1529. doi: 10.1038/s41598-020-80325-x

  • CrossRef
  • Google Scholar

• 245

  LarssonP. T.SchwielerJ. H.WallenN. H. (2000). Platelet activation during angiotensin II infusion in healthy volunteers. Blood Coag. Fibrinolysis11, 61–69. doi: 10.1097/00001721-200011010-00007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  LavrentyevE. N.MalikK. U. (2009). High glucose-induced Nox1-derived superoxides downregulate PKC-βII, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs. Am. J. Physiol. Circ. Physiol.296, H106–H118. doi: 10.1152/ajpheart.00239.2008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 247

  LeeI. I.NakayamaT.WuC. T.GoltseyY.JiangS.GallP. A.et al. (2020). ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. Nat. Commun.11:5453. doi: 10.1038/s41467-020-19145-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  LeiC.QianK.LiT.ZhangS.FuW.DingM.et al. (2020). Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig. Nat. Commun.11:2070. doi: 10.1038/s41467-020-16048-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  Leonard-LorantI.DelabrancheX.SeveracF.HelmsJ.PauzetC.CollangeO.et al. (2020). Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels. Radiology296, E189–E191. doi: 10.1148/radiol.2020201561

  • CrossRef
  • Google Scholar

• 250

  LiZ.FergusonA. V. (1993). Subfornical organ efferents to paraventricular nucleus utilize angiotensin as a neurotransmitter. Am. J. Phys. Regul. Integr. Comp. Phys.265, R302–R309. doi: 10.1152/ajpregu.1993.265.2.R302

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 251

  LiG.HeX.ZhangL.RanQ.WangJ.XiongA.et al. (2020). Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19. J. Autoimmun.112:102463. doi: 10.1016/j.jaut.2020.102463

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  LiL.HuangM.ShenJ.WangY.WangR.YuanC.et al. (2021). Serum levels of soluble platelet endothelial cell adhesion molecule 1 in COVID-19 patients are associated with disease severity. J. Infect. Dis.223, 178–179. doi: 10.1093/infdis/jiaa642

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 253

  LiW.MooreM. J.VasilievaN.SuiJ.WongS. K.BerneM. A.et al. (2003). Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature426, 450–454. doi: 10.1038/nature02145

  • CrossRef
  • Google Scholar

• 254

  LiW.SuiJ.HuangI. C.KuhnJ. H.RadoshitzkyS. R.MarascoW. A.et al. (2007). The S proteins of human coronavirus NL63 and severe acute respiratory syndrome coronavirus bind overlapping regions of ace2. Virology367, 367–374. doi: 10.1016/j.virol.2007.04.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 255

  LindnerD.FitzekA.BräuningerH.AleshchevaG.EdlerC.MeissnerK.et al. (2020). Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases. JAMA Cardiol.5, 1281–1285. doi: 10.1001/jamacardio.2020.3551

  • CrossRef
  • Google Scholar

• 256

  LippiG.FavaloroE. J. (2020). D-dimer is associated with severity of coronavirus disease 2019: a pooled analysis. Thromb. Haemost.120, 876–878. doi: 10.1055/s-0040-1709650

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 257

  LiuY.HuG.WangY.RenW.ZhaoX.JiF.et al. (2021). Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2. Proc. Natl. Acad. Sci. U. S. A.118:e2025373118. doi: 10.1073/pnas.2025373118

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 258

  LiuC.LiY.GuanT.LaiY.ShenY.ZeyaweidingA.et al. (2018). ACE2 polymorphisms associated with cardiovascular risk in Uygurs with type 2 diabetes mellitus. Cardiovasc. Diabetol.17:127. doi: 10.1186/s12933-018-0771-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 259

  LiuC.LuoR.ElliottS. E.WangW.ParchimN. F.IriyamaT.et al. (2015). Elevated transglutaminase activity triggers angiotensin receptor activating autoantibody production and pathophysiology of preeclampsia. J. Am. Heart Assoc.4:e002323. doi: 10.1161/JAHA.115.002323

  • CrossRef
  • Google Scholar

• 260

  LiuP.WysockiJ.SoumaT.YeM.RamirezV.ZhouB.et al. (2018). Novel ACE2-fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation. Kidney Int.94, 114–125. doi: 10.1016/j.kint.2018.01.029

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  LiuY.YangY.ZhangC.HuangF.WangF.YuanJ.et al. (2020). Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci. China Life Sci.63, 364–374. doi: 10.1007/s11427-020-1643-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 262

  LiuY.ZhangH. G. (2021). Vigilance on new-onset atherosclerosis following SARS-CoV-2 infection. Front. Med.7:629413. doi: 10.3389/fmed.2020.629413

  • CrossRef
  • Google Scholar

• 263

  LongQ. X.LiuB. Z.DengH. J.WuG. C.DengK.ChenY. K.et al. (2020). Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat. Med.26, 845–848. doi: 10.1038/s41591-020-0897-1

  • CrossRef
  • Google Scholar

• 264

  LopezR. D.MacedoA. V. S.de BarosE.SilvaP. G. M.Moll-BernardesJ.dos SantosT.et al. (2021). Continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19. A randomized clinical trial. JAMA325, 254–264. doi: 10.1001/jama.2020.25864

  • CrossRef
  • Google Scholar

• 265

  LorenteL.MartınM. M.FrancoA.BarriosY.CaceresJ. J.Solé-ViolánJ.et al. (2020). HLA genetic polymorphisms and prognosis of patients with COVID-19. Med. Int.45, 96–103. doi: 10.1016/j.medin.2020.08.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  LuanJ.LuY.JinX.ZhangL. (2020). Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARSCoV-2 infection. Biochem. Biophys. Res. Commun.526, 165–169. doi: 10.1016/j.bbrc.2020.03.047

  • CrossRef
  • Google Scholar

• 267

  LubbeL.CozierG. E.DosthuizenD.AcharyaK. R.SturrockE. D. (2020). ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV. Clin. Sci.134, 2851–2871. doi: 10.1042/CS20200899

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 268

  LuoY.LiuC.GuanT.LiY.LaiY.LiF.et al. (2019). Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in South Xinjiang. Hypertens. Res.42, 681–689. doi: 10.1038/s41440-018-0166-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 269

  LuoY.MaoL.YanX.XueY.LinQ.TangG.et al. (2020). Predicted model based on the combination of cytokines and lymphocytes subsets for prognosis of SARS-CoV-2 infection. J. Clin. Immunol.40, 960–969. doi: 10.1007/s10875-020-00821-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 270

  LutherJ. M.GainerJ. V.MurpheyL. J.YuC.VaughanD. E.MorrowJ. D.et al. (2006). Hypertension48, 1050–1057. doi: 10.1161/01.HYP.0000248135.97380.76

  • CrossRef
  • Google Scholar

• 271

  LvY.LiY.YiY.ZhangL.ShiQ.YangJ. (2018). A genomic survey of angiotensin-converting enzymes provides novel insights into their molecular evolution in vertebrates. Moelcules23:2923. doi: 10.3390/molecules23112923

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  MaH.ZengW.HeH.ZhaoD.JiangD.ZhouP.et al. (2020). Serum IgA, IgM, and IgG responses in COVID-19. Cell. Mol. Immunol.17, 773–775. doi: 10.1038/s41423-020-0474-z

  • CrossRef
  • Google Scholar

• 273

  MagroC.MulveyJ. J.BerlinD.NuovoG.SalvatoreS.HarpJ.et al. (2020). Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl. Res.220, 1–13. doi: 10.1016/j.trsl.2020.04.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 274

  MaitiB. K. (2021). Bioengineered angiotensin-converting-enzyme-2: a potential therapeutic option against SARS-CoV-2 infection. J. Hum. Hypertens.36, 488–492. doi: 10.1038/s41371-021-00636-y

  • CrossRef
  • Google Scholar

• 275

  ManneB. K.DenormeF.MiddletonE. A.PortierI.RowleyJ. W.StubbenC. J.et al. (2020). Platelet gene expression and function in COVID-19 patients. Blood136, 1317–1329. doi: 10.1182/-blood.2020007214

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 276

  MarchianoS.HsiangT. Y.KhannaA.HigashiT.WhitmoreL. S.BargehrJ.et al. (2021). SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function. Stem Cell Rep.16, 478–492. doi: 10.1016/j.stemcr.2021.02.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 277

  MarianA. J. (2013). The discovery of the ACE2 gene. Circ. Res.112, 1307–1309. doi: 10.1161/CIRCRESAHA.113.301271

  • CrossRef
  • Google Scholar

• 278

  MarraM. A.JonesS. J.AstellC. R.HoltR. A.Brooks-WilsonA.ButterfieldY. S.et al. (2003). The genome sequence of the SARS-associated coronavirus. Science300, 1399–1404. doi: 10.1126/science.1085953

  • CrossRef
  • Google Scholar

• 279

  MarshallR. P.WebbS.BellinganG. J.MontgomeryH. E.ChaudhariB.Mc ArthurR. J.et al. (2002). Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med.166, 646–650. doi: 10.1164/rccm.2108086

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 280

  MartinezE.PuraA.EscribanoJ.SanchisC.CarrionL.ArtigaoM.et al. (2000). Angiotensin-converting enzyme (ACE) gene polymorphisms, serum ACE activity and blood pressure in a Spanish-Mediterranean population. J. Hum. Hypertens.14, 131–135. doi: 10.1038/sj.jhh.1000958

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 281

  Martinez-RojasM. A.Vega-VegaO.BobadillaX. N. A. (2020). Is the kidney a target of SARS-CoV-2?Am. J. Physiol. Ren. Physiol.318, F1454–F1462. doi: 10.1152/AJPRENAL.00160.2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 282

  MartinsA. L. V.da SilvaF. A.Bolais-RamosL.Capanema de OliveiraG.Cunha RibeiroR.Alves PereiraD. A.et al. (2021). Increased circulating levels of angiotensin-(1–7) in severely ill COVID-19 patients. ERJ Open Res.7, 00114–02021. doi: 10.1183/23120541.00114-2021

  • CrossRef
  • Google Scholar

• 283

  Martin-SanchosL.LewinskiM. K.PacheL.StonehamC. A.YinX.BeckerM.et al. (2021). Functional landscape of SARS-CoV-2 cellular restriction. Mol. Cell81, 2656–2668.e8. doi: 10.1016/j.molcel.2021.04.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 284

  MassiéraF.Bloch-FaureM.CeilerD.MurakamiK.FukamizuA.GascJ.-M.et al. (2001). Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. FASEB J.15, 2727–2729. doi: 10.1096/fj.01-0457fje

  • CrossRef
  • Google Scholar

• 285

  MeccaA. P.RegenhardtR. W.O'ConnorT. E.JospehJ. P.RaizadaM. K.KatovichM. J.et al. (2011). Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke. Exp. Physiol.96, 1084–1096. doi: 10.1113/expphysiol.2011.058578

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 286

  MehtaP.Mc AutleyD. F.BrownM.SanchezE.TattersallR. S.MansonJ. J.et al. (2020). COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet395, 1033–1034. doi: 10.1016/S0140-6736(20)30628-0

  • CrossRef
  • Google Scholar

• 287

  MengJ.XiaoG.ZhangJ.HeX.OuM.BiJ.et al. (2020). Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg. Microb. Infect.9, 757–760. doi: 10.1080/22221751.2020.1746200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 288

  MengN.ZhangY.MaJ.LiH.ZhouF.QuY. (2015). Association of polymorphisms of angiotensin I converting enzyme 2 with retinopathy in type 2 diabetes mellitus among Chinese individuals. Eye29, 266–271. doi: 10.1038/eye.2014.254

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 289

  MentzR. J.BakrisG. L.WaeberB.McMurrayJ. J.GheorghiadeM.RuilopeL. M.et al. (2013). The past, present and future of renin-angiotensin aldosterone system inhibition. Int. J. Cardiol.167, 1677–1687. doi: 10.1016/j.ijcard.2012.10.007

  • CrossRef
  • Google Scholar

• 290

  MiddeldorpS.CoppensM.van HaapsT. F.FoppenM.VlaarA. P.MillerM. C. A.et al. (2020). Incidence of venous thromboembolism in hospitalized patients with COVID-19. J. Thromb. Haemost.18, 1995–2002. doi: 10.1111/jth.14888

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 291

  MiedemaJ.SchreursM.van der Sarvan der BruggeS.PaatsM.BaartS.BakkerM.et al. (2021). Antibodies against angiotensin II receptor type 1 and endothelin a receptor are associated with an unfavorable COVID19 disease course. Front. Immunol.12:684142. doi: 10.3389/fimmu.2021.684142

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 292

  MinatoT.NirasawaS.SatoT.YamaguchiT.HoshizakiM.InagakiT.et al. (2020). B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction. Nat. Commun.11:1058. doi: 10.1038/s41467-020-14867-z

  • CrossRef
  • Google Scholar

• 293

  MizuiriS.HemmiH.AritaM.OhashiY.TanakaY.MiyagiM.et al. (2008). Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls. Am. J. Kidney Dis.51, 613–623. doi: 10.1053/j.ajkd.2007.11.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 294

  MöhlendickB.SchönfelderK.BreuckmannK.ElsnerC.BabelN.BalfanzP.et al. (2021). ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19. Pharmacogenet. Genomics31, 165–171. doi: 10.1097/FPC.0000000000000436

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 295

  MontagutelliXProtMLevillayerLBaquero SAlazarEJouvionGConquetL.et al. The B1.351 and P. 1 variants extend SARS-CoV-2 host range to mice. bioRxiv [Preprint]. (2021). doi: 10.1101/2021.03.18.436013

  • CrossRef
  • Google Scholar

• 296

  MonteilV.DyczynskiM.LauschkeV. M.KwonH.WirnsbergerG.YouhannaS.et al. (2021). Human soluble ACE2 improves the effect of remdesivir in SARS-CoV-2 infection. EMBO Mol. Med.13:e13426. doi: 10.15252/emmm.202013426

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 297

  MooreJ. P.VinhA.TuckK.SakkalS.KrishnanS. M.ChanC. T.et al. (2015). M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure. Am. J. Physiol. Circ. Physiol.309, H906–H917. doi: 10.1152/ajpheart.00821.2014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 298

  MullerD. N.HilgersK. F.MathewsS.BreuV.FischliW.UhlmannR.et al. (1999). Effects of human prorenin in rats transgenic for human angiotensinogen. Hypertension33, 312–317. doi: 10.1161/01.HYP.33.1.312

  • CrossRef
  • Google Scholar

• 299

  MullerD. N.MervaalaE. M. A.DechendR.FiebelerA.ParkJ. K.SchmidtF.et al. (2000). Angiotensin II (AT₁) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. Am. J. Pathol.157, 111–122. doi: 10.1016/S0002-9440(10)64523-3

  • CrossRef
  • Google Scholar

• 300

  MullickA. E.YehS. T.GrahamM. J.EngelhardtJ. A.PrakashT. P.CrookeR. M. (2017). Blood pressure lowering and safety improvements with liver angiotensinogen inhibition in models of hypertension and kidney injury. Hypertension70, 566–576. doi: 10.1161/HYPERTENSIONAHA.117.09755

  • CrossRef
  • Google Scholar

• 301

  MurphyT. J.AlexanderR. W.GriendlingK. K.RungeM. S.BernsteinK. E. (1991). Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature351, 233–236. doi: 10.1038/351233a0

  • CrossRef
  • Google Scholar

• 302

  MuusCLueckenMEraslanGWaghrayAHeimbergGSikkemaLet al. (2020). Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells. bioRxiv [Preprint]. doi: 10.1101/2020.04.19.049254

  • CrossRef
  • Google Scholar

• 303

  NabahY. N. A.MateoT.EstellésR.MataM.ZagorskiJ.SarauH.et al. (2004). Angiotensin II induces neutrophil accumulation in vivo through generation and release of CXC chemokines. Circulation110, 3581–3586. doi: 10.1161/01.CIR.0000148824.93600.F3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 304

  NaftilanA. J.OparilS. (1978). Inhibition of renin release from rat kidney slices by the angiotensins. Am. J. Phys.235, F62–F68. doi: 10.1152/ajprenal.1978.235.1.F62

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 305

  NassarH.LaviE.AkkawiS.BdeirK.HeymanS. M.RaghunathP. N.et al. (2007). Alpha-Defensin: link between inflammation and atherosclerosis. Atherosclerosis194, 452–457. doi: 10.1016/j.atherosclerosis.2006.08.046

  • CrossRef
  • Google Scholar

• 306

  NatarajC.OliverioM. I.MannonR. B.MannonP. J.AudolyL. P.AmuchasteguiC. S.et al. (1999). Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J. Clin. Invest.104, 1693–1701. doi: 10.1172/JCI7451

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 307

  NemersonY. (1988). Tissue factor and hemostasis. Blood71, 1–8. doi: 10.1182/blood.V71.1.1.1

  • CrossRef
  • Google Scholar

• 308

  NevesF. A.DuncanK. G.BaxterJ. D. (1996). Cathepsin B is a prorenin processing enzyme. Hypertension27, 514–517. doi: 10.1161/01.hyp.27.3.514

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 309

  NguyenA.DavidJ. K.MadenS. K.WoodM. A.WeederB. R.NelloreA.et al. (2020). Human leukocyte antigen susceptibility map for severe acute respiratory syndrome coronavirus 2. J. Virol.94, e00510–e00520. doi: 10.1128/JVI.00510-20

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 310

  NguyenG.DelarueF.BurckléC.BouzhirL.GillerT.SraerJ. D. (2002). Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest.109, 1417–1427. doi: 10.1172/JCI14276

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 311

  NikiforukA. M.KuchinskiK. S.TwaD. D. W.LukacC. D.SbihiH.BashamC. A.et al. (2021). The contrasting role of nasopharyngeal angiotensin converting enzyme 2 (ACE2) expression in SARS-CoV-2 infection: a cross-sectional study of people tested for COVID-19 in British Columbia. EBio Med.66:103316. doi: 10.1016/j.ebiom.2021.103316

  • CrossRef
  • Google Scholar

• 312

  NishimuraH. (2017). Renin-angiotensin system in vertebrates: phylogenetic view of structure and function. Anat. Sci. Int.92, 215–247. doi: 10.1007/s12565-016-0372-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 313

  NishimuraH.TsujiH.MasuadaH.NakagawaK.NakaharaY.KitamuraH.et al. (1997). Angiotensin II increases plasminogen activator Inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. Thromb. Haemost.77, 1189–1195. doi: 10.1055/s-0038-1656136

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 314

  NiuW.QiY.HouS.ZhouW.QiuC. (2007). Correlation of angiotensin-converting enzyme 2 gene polymorphisms with stage 2 hypertension in Han Chinese. Transl. Res.150, 374–380. doi: 10.1016/j.trsl.2007.06.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 315

  OarheC. I.DangV.DangM. T.NguyenH.GopallawaI.GewolbI. H.et al. (2015). Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts. Pediatr. Res.77, 656–662. doi: 10.1038/pr.2015.27

  • CrossRef
  • Google Scholar

• 316

  OnabajoO. O.BandayA. R.StaniferM. L.YanW.ObajemuA.SanterD. M.et al. (2020). Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor. Nat. Genet.52, 1283–1293. doi: 10.1038/s41588-020-00731-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 317

  OrtizM. E.ThurmanA.PezzuloA. A.LeidingerM. R.Klesney-TaitJ. A.KarpP. H.et al. (2020). Heterogeneous expression of the SARS Coronavirus-2 receptor ACE2 in the human respiratory tract. EBioMed.60:102976. doi: 10.1016/j.ebiom.2020.102976

  • CrossRef
  • Google Scholar

• 318

  Ortiz-FernándezL.SawalhaA. H. (2020). Genetic variability in the expression of the SARS-CoV-2 host cell entry factors across populations. Genes Immun.21, 269–272. doi: 10.1038/s41435-020-0107-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 319

  OsmanI. O.GarrecC.de SouzaG. A. P.ZarubicaA.BelhaouariD. B.BaudoinJ.-P.et al. (2022). Control of CDH1/E-cadherin gene expression and release of a soluble form of E-cadherin in SARS-CoV-2 infected Caco-2 intestinal cells: Physiopathological consequences for the intestinal forms of COVID-19. Front. Cell. Infect. Microbiol.12:798767. doi: 10.3389/fcimb.2022.798767

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 320

  OsmanI. O.MelenotteC.BrouquiP.MillionM.LagierJ.-C.ParolaP.et al. (2021). Expression of ACE2, soluble ACE2, angiotensin I, angiotensin II and angiotensin-(1-7) is modulated in COVID-19 patients. Front. Immunol.12:625732. doi: 10.3389/fimmu.2021.625732

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 321

  OthmanH.BouslamaZ.BrandenburgJ. T.da RochaJ.HamdiY.GhediraK.et al. (2020). Interaction of the spike protein RBD from SARS-CoV-2 with ACE2: similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism. Biochem. Biophys. Res. Commun.527, 702–708. doi: 10.1016/j.bbrc.2020.05.028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 322

  Oude MunninkB. B.SikkemaR. S.NieuwenhuijseD. F.MolenaarR. J.MungerE.MolenkampR.et al. (2021). Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans. Science371, 172–177. doi: 10.1126/science.abe5901

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 323

  OuditG. Y.CrackowerM. A.BackxP. H.PenningerJ. M. (2003). The role of ACE2 in cardiovascular physiology. Trends Cardiovasc. Med.13, 93–101. doi: 10.1016/s1050-1738(02)00233-5

  • CrossRef
  • Google Scholar

• 324

  OuditG. Y.LiuG. C.ZhongJ.BasuR.ChowF. L.ZhouJ.et al. (2010). Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes59, 529–538. doi: 10.2337/db09-1218

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 325

  OuditG. Y.PfefferM. A. (2020). Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19. Eur. Heart J.41, 1818–1820. doi: 10.1093/eurheartj/ehaa414

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 326

  PageI. H.HelmerO. M. (1940). Angiotonin-activator, renin-and angiotonin-inhibitor, and the mechanism of angiotonin tachyphylaxis in normal, hypertensive, and nephrectomized animals. J. Exp. Med.71, 495–519. doi: 10.1084/jem.71.4.495

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 327

  Pairo-CastineiraE.ClohiseyS.KlaricL.BretherickA.RawlikK.ParkinsonN.et al. (2021). Genetic mechanisms of critical illness in Covid-19. Nature591, 92–98. doi: 10.1038/s41586-020-03065-y

  • CrossRef
  • Google Scholar

• 328

  PatelS. K.VelkoskaE.FreemanM.WaiB.LancefieldT. F.BurrellL. M. (2014). From gene to protein - experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension. Front. Physiol.5:227. doi: 10.3389/fphys.2014.00227

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 329

  PatelV. B.ZhongJ. C.GrantM. B.OuditG. Y. (2016). Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ. Res.118, 1313–1326. doi: 10.1161/CIRCRESAHA.116.307708

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 330

  PatnaikM.PatiP.SwainS. N.MohapatraM. K.DwibediB.KarS. K.et al. (2014). Association of angiotensinconverting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha, India. Ann. Hum. Biol.41, 145–152. doi: 10.3109/03014460.2013.837195

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 331

  PaulM.Poyan MehrA.KreutzR. (2006). Physiology of local renin-angiotensin systems. Physiol. Rev.86, 747–803. doi: 10.1152/physrev.00036.2005

  • CrossRef
  • Google Scholar

• 332

  PedersenK. B.ChhabraK. H.NguyenV. K.XiaH.LazartiguesE. (2013). The transcription factor HNF1alpha induces expression of angiotensin-converting enzyme 2 (ACE2) in pancreatic islets from evolutionarily conserved promoter motifs. Biochim. Biophys. Acta1829, 1225–1235. doi: 10.1016/j.bbagrm.2013.09.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 333

  Pena SilvaR. A.ChuY.MillerJ. D.MitchellI. J.PenningerJ. M.FaraciF. M.et al. (2012). Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging. Stroke43, 3358–3363. doi: 10.1161/STROKEAHA.112.667063

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 334

  PengH.LiW.SethD. M.NairA. R.FrancisJ.FengY. (2013). (pro)renin receptor mediates both angiotensin II-dependent and-independent oxidative stress in neuronal cells. PLoS One8:e58339. doi: 10.1371/journal.pone.0058339

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 335

  PerlotT.PenningerJ. M. (2013). ACE2-from the renin-angiotensin system to gut microbiota and malnutrition. Microbes Infect.15, 866–873. doi: 10.1016/j.micinf.2013.08.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 336

  PhillipsM. I.Schmidt-OttK. M. (1999). The discovery of renin 100 years ago. News Physiol. Sci.14, 271–274. doi: 10.1152/physiologyonline.1999.14.6.271

  • CrossRef
  • Google Scholar

• 337

  PhilogeneM. C.JohnsonT.VaughtA. J.ZakariaS.FedarkoN. (2019). Antibodies against angiotensin II type 1 and endothelin a receptors: relevance and pathogenicity. Hum. Immunol.80, 561–567. doi: 10.1016/j.humimm.2019.04.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 338

  PierceJ. B.SimionV.IcliB.Perez-CremadesD.ChengH. S.FeinbergM. W. (2020). Computational analysis of targeting SARS-CoV-2, viral entry proteins ACE2 and TMPRSS2, and interferon genes by host MicroRNAs. Genes (Basel)11:1354. doi: 10.3390/genes11111354

  • CrossRef
  • Google Scholar

• 339

  PinheiroD. S.SantosR. S.JardimP. C. B. V.SilvaE. G.ReisA. A. S.PedrinoG. R.et al. (2019). The combination of ACE I/D and ACE2 G8790A polymorphisms reveals susceptibility to hypertension: a genetic association study in Brazilian patients. PLoS One14:e0221248. doi: 10.1371/journal.pone.0221248

  • CrossRef
  • Google Scholar

• 340

  PintoB. G. G.OliveiraA. E. R.SinghY.JimenezL.GonçalvesA. N. A.OgavaR. L. T.et al. (2020). ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19. J. Infect. Dis.222, 556–563. doi: 10.1093/infdis/jiaa332

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 341

  Pires de SouzaG. A.OsmanI. O.Le BideauM.BaudoinJ.-P.JaafarR.DevauxC.et al. (2022). Angiotensin II receptor blockers (ARBs antihypertensive agents) increase replication of SARS-CoV-2 in Vero E6 cells. Front. Cell. Infect. Microbiol.11:639177. doi: 10.3389/fcimb.2021.639177

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 342

  PoissyJ.GoutayJ.CaplanM.ParmentierE.DuburcqT.LassaleF.et al. (2020). Pulmonary embolism in patients with COVID19. Circulation142, 184–186. doi: 10.1161/CIRCULATIONAHA.120.047430

  • CrossRef
  • Google Scholar

• 343

  PouladiN.AbdolahiS. (2021). Investigating the ACE2 polymorphisms in COVID-19 susceptibility: An in silico analysis. Mol. Genet. Genom. Med.9:e1672. doi: 10.1002/mgg3.1672

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 344

  PrajapatM.ShekharN.SarmaP.AvtiP.SinghS.KaurH.et al. (2020). Virtual screening and molecular dynamics study of approved drugs as inhibitors of spike protein S1 domain and ACE2 interaction in SARS-CoV-2. J. Mol. Graph. Model.101:107716. doi: 10.1016/j.jmgm.2020.107716

  • CrossRef
  • Google Scholar

• 345

  PrietoM. C.Gonzalez-VillalobosR. A.BotrosF. T.MartinV. L.PaganJ.SatouR.et al. (2011). Reciprocal changes in renal ACE/ANG II and ACE2/ANG 1-7 are associated with enhanced collecting duct renin in Goldblatt hypertensive rats. Am. J. Physiol. Ren. Physiol.300, F749–F755. doi: 10.1152/ajprenal.00383.2009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 346

  ProckoE. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2. bioRxiv [Preprint]. (2020). doi: 10.1101/2020.1103.1116.994236

  • CrossRef
  • Google Scholar

• 347

  QaradakhiT.GadanecL. (2020). Could DIZE be the answer to COVID-19?Maturitas140, 83–84. doi: 10.1016/j.maturitas.2020.07.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 348

  QiY. F.ZhangJ.Cole-JeffreyC. T.ShenoyV.EspejoA.HannaM.et al. (2013). Diminazene Aceturate enhances angiotensin-converting enzyme 2 activity and attenuates ischemia-induced cardiac pathophysiology. Hypertension62, 746–752. doi: 10.1161/HYPERTENSIONAHA.113.01337

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 349

  QiaoY.WangX. M.MannanR.PitchiayaS.ZhangY.WotringJ. W.et al. (2021). Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2. Proc. Natl. Acad. Sci. U. S. A.118:e2021450118. doi: 10.1073/pnas.2021450118

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 350

  QiuY.ShilP. K.ZhuP.YangH.VermaA.LeiB.et al. (2014). Angiotensin-converting enzyme 2 (ACE2) activator Diminazene Aceturate ameliorates endotoxin-induced uveitis in mice. Invest. Ophthalmol. Vis. Sci.55, 3809–3818. doi: 10.1167/iovs.14-13883

  • CrossRef
  • Google Scholar

• 351

  QiuY.ZhaoY. B.WangQ.LiJ. Y.ZhouZ. J.LiaoC. H.et al. (2020). Predicting the angiotensin converting enzyme 2 (ACE2) utilizing capability as the receptor of SARS-CoV-2. Microbes Infect.22, 221–225. doi: 10.1016/j.micinf.2020.03.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 352

  RadzikowskaU.DingM.TanG.ZhakparovD.PengY.WawrzyniakP.et al. (2020). Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy75, 2829–2845. doi: 10.1111/all.14429

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 353

  RaghavanS.KenchappaD. B.LeoM. D. (2021). SARS-CoV-2 spike protein induces degradation of junctional proteins that maintain endothelial barrier integrity. Front. Cardiovasc. Med.8:687783. doi: 10.3389/fcvm.2021.687783

  • CrossRef
  • Google Scholar

• 354

  RajagopalS.RajagopalK.LefkowitzR. J. (2010). Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat. Rev. Drug Discov.9, 373–386. doi: 10.1038/nrd3024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 355

  ReichH. N.OuditG. Y.PenningerJ. M.ScholeyJ. W.HerzenbergA. M. (2008). Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease. Kidney Int.74, 1610–1616. doi: 10.1038/ki.2008.497

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 356

  Reindl-SchwaighoferR.HödlmoserS.EskandaryF.PoglitschM.BondermanD.StrasslR.et al. (2021). ACE2 elevation in severe COVID-19. Am. J. Resp. Critic. Care Med.203, 1191–1196. doi: 10.1164/rccm.202101-0142LE

  • CrossRef
  • Google Scholar

• 357

  RenW.LanJ.JuX.GongM.LongQ.ZhuZ.et al. (2021). Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption. PLoS Pathog.17:e1010053. doi: 10.1371/journal.ppat.1010053

  • CrossRef
  • Google Scholar

• 358

  RiceG. I.JonesA. L.GrantP. J.CarterA. M.TurnerA. J.HooperN. M. (2006). Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension48, 914–920. doi: 10.1161/01.HYP.0000244543.91937.79

  • CrossRef
  • Google Scholar

• 359

  RiederM.WirthL.PollmeierL.JeserichM.GollerI.BaldusN.et al. (2021). Serum ACE2, angiotensin II, and aldosterone levels are unchanged in patients with COVID-19. Am. J. Hypertens.34, 278–281. doi: 10.1093/ajh/hpaa169

  • CrossRef
  • Google Scholar

• 360

  RiordanJ. F. (2003). Angiotensin-I-converting enzyme and its relatives. Genome Biol.4:225. doi: 10.1186/gb-2003-4-8-225

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 361

  RivièreG.MichaudA.CorradiH. R.SturrockE. D.AcharyaK. R.CoqezV.et al. (2007). Characterization of the first angiotensin-converting like enzyme in bacteria: ancestor ACE is already active. Gene399, 81–91. doi: 10.1016/j.gene.2007.05.010

  • CrossRef
  • Google Scholar

• 362

  RobinsonF. A.MihealsickR. P.WagenerB. M.HannaP.PostonM. D.EfimovI. R.et al. (2020). Role of angiotensin-converting enzyme 2 and pericytes in cardiac complications of COVID-19 infection. Am. J. Physiol. Heart Circ. Physiol.319, H1059–H1068. doi: 10.1152/ajpheart.00681.2020

  • CrossRef
  • Google Scholar

• 363

  Rodriguez RodriguezM.Castro QuismondoN.Zafra TorresD.Gil AlosD.AyalaR.Martinez-LopezJ. (2021). Increased von Willebrand factor antigen and low ADAMTS13 activity are related to poor prognosis in covid-19 patients. Int. J. Lab. Hematol.43, O152–O155. doi: 10.1111/ijlh.13476

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 364

  RotaP. A.ObersteM. S.MonroeS. S.NixW. A.CampagnoliR.IcenogleJ. P.et al. (2003). Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science300, 1394–1399. doi: 10.1126/science.1085952

  • CrossRef
  • Google Scholar

• 365

  RovasA.OsiaeviI.BuscherK.SackarndJ.TepasseP. R.FobkerM.et al. (2020). Microvascular dysfunction in COVID-19: the MYSTIC study. Angiogenesis24, 145–157. doi: 10.1007/s10456-020-09753-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 366

  Ruiz-OrtegaM.LorenzoO.SuzukiY.Rupe’rezM.EgidoJ. (2001). Proinflammatory actions of angiotensins. Curr. Opin. Nephrol. Hypertens.10, 321–329. doi: 10.1097/00041552-200105000-00005

  • CrossRef
  • Google Scholar

• 367

  RushworthC. A.GuyJ. L.TurnerA. J. (2008). Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting enzymes (ACE and ACE2) identified by site-directed mutagenesis. FEBS J.275, 6033–6042. doi: 10.1111/j.1742-4658.2008.06733.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 368

  RyszS.Al-SaadiJ.SjöströmA.FarmM.Campoccia JaldeF.PlatténM.et al. (2021). COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system. Nat. Commun.12:2417. doi: 10.1038/s41467-021-22713-z|

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 369

  SadoshimaJ.QiuZ. H.MorganJ. P.IzumoS. (1995). Angiotensin-II and other hypertrophic stimuli mediated by G-protein-coupled receptors activate tyrosine kinase, mitogen-activated protein-kinase, and 90-Kd S6 kinase in cardiac myocytes - the critical role of Ca2+−dependent signaling. Circ. Res.76, 1–15. doi: 10.1161/01.res.76.1.1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 370

  SakkaM.ConnorsJ. M.He KimianG.Martin-ToutainI.CrichiB.ColmegnaI.et al. (2020). Association between D-dimer levels and mortality in patients with coronavirus disease 2019 COVID19: a systematic review and pooled analysis. J. Med. Vasc.45, 268–274. doi: 10.1016/j.jdmv.2020.05.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 371

  SamaI. E.RaveraA.SantemaB. T.van GoorH.ter MaatenJ. M.ClelandJ. G. F.et al. (2020). Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors. Eur. Heart J.41, 1810–1817. doi: 10.1093/eurheartj/ehaa373

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 372

  SamavatiL.UhalB. D. (2020). ACE2, much more than just a receptor for SARS-COV-2. Front. Cell. Infect. Microbiol.10:317. doi: 10.3389/fcimb.2020.00317

  • CrossRef
  • Google Scholar

• 373

  SantosR. A. S.SampaioW. O.AlzamoraA. C.Motta-SantosD.AleninaN.BaderM.et al. (2018). The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7). Physiol. Rev.98, 505–553. doi: 10.1152/physrev.00023.2016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 374

  SantosR. A.Silva ACS. E.MaricC.DMRS.MachadoR. P.de BuhrI.et al. (2003). Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc. Natl. Acad. Sci. U. S. A.100, 8258–8263. doi: 10.1073/pnas.1432869100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 375

  SarzaniR.GiuliettiF.Di PentimaC.FilipponiA.SpannellaF. (2020). Antagonizing the renin-angiotensin-aldosterone system in the era of COVID-19. Intern. Emerg. Med., 15, 885–887. doi: 10.1007/s11739-020-02365-5

  • CrossRef
  • Google Scholar

• 376

  SatoT.SuzukiT.WatanabeH.KadowakiA.FukamizuA.LiuP. P.et al. (2013). Apelin is a positive regulator of ACE2 in failing hearts. J. Clin. Invest.123, 5203–5211. doi: 10.1172/JCI69608

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 377

  Sayed-TabatabaeiF. A.OostraB. A.IsaacsA.van DuijnC. M.WittemanJ. C. M. (2006). ACE polymorphism. Circ. Res.98, 1123–1133. doi: 10.1161/01.RES.0000223145.74217.e7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 378

  SchiffrinE. L.FlackJ. M.ItoS.MuntnerP.WebbR. C. (2020). Hypertension and COVID-19. Am. J. Hypertens.33, 373–374. doi: 10.1093/ajh/hpaa057

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 379

  SchmidtS.van HooftI. M.GrobbeeD. E.GantenD.RitzE. (1993). Polymorphism of the angiotensin I converting enzyme gene is apparently not related to high blood pressure: Dutch hypertension and offspring study. J. Hypertens.11, 345–348. doi: 10.1097/00004872-199304000-00003

  • CrossRef
  • Google Scholar

• 380

  Schmidt-OttK. M.KagiyamaS.PhilipsM. I. (2000). The multiple actions of angiotensin II in atherosclerosis. Regul. Pept.93, 65–77. doi: 10.1016/s0167-0115(00)00178-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 381

  SchmiederR. E.HilgersK. F.SchlaichM. P.SchmidtB. M. W. (2007). Renin-angiotensin system and cardiovascular risk. Lancet369, 1208–1219. doi: 10.1016/S0140-6736(07)60242-6

  • CrossRef
  • Google Scholar

• 382

  SealeyJ. E.RubattuS. (1989). Prorenin and renin as separate mediators of tissue and circulating systems am. J. Hypertens.2, 358–366. doi: 10.1093/ajh/2.5.358

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 383

  SenchenkovaE. Y.RussellJ.Almeida-PaulaL. D.HardingJ. W.GrangerD. N. (2010). Angiotensin II-mediated microvascular thrombosis. Hypertension56, 1089–1095. doi: 10.1161/HYPERTENSIONAHA.110.158220

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 384

  SenchenkovaE. Y.RussellJ.EsmonC. T.GrangerD. N. (2014). Roles of coagulation and fibrinolysis in angiotensin II enhanced microvascular thrombosis. Microcirculation21, 401–407. doi: 10.1111/micc.12120

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 385

  ShangJ.YeG.ShiK.WanY.LuoC.AiharaH.et al. (2020). Structural basis of receptor recognition by SARS-CoV-2. Nature581, 221–224. doi: 10.1038/s41586-020-2179-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 386

  ShenL.MoH.CaiL.KongT.ZhengW.YeJ.et al. (2009). Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases. Shock31, 500–506. doi: 10.1097/SHK.0b013e318189017a

  • CrossRef
  • Google Scholar

• 387

  ShenQ.XiaoX.AierkenA.YueW.WuX.LiaoM.et al. (2020). The ACE2 expression in Sertoli cells and germ cells may cause male reproductive disorder after SARS-CoV-2 infection. J. Cell. Mol. Med.24, 9472–9477. doi: 10.1111/jcmm.15541

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 388

  ShenoyV.GjymishkaA.JarajapuY. P.QiY.AfzalA.RigattoK.et al. (2013). Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. Am. J. Respir. Crit. Care Med.187, 648–657. doi: 10.1164/rccm.201205-0880OC

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 389

  ShermanE. J.EmmerB. T. (2021). ACE2 protein expression within isogenic cell lines is heterogeneous and associated with distinct transcriptomes. Sci. Rep.11:15900. doi: 10.1038/s41598-021-95308-9

  • CrossRef
  • Google Scholar

• 390

  ShiltsJ.CrozierT. W. M.GreenwoodE. J. D.LehnerP. J.WrightG. J. (2021). No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. Sci. Rep.11:413. doi: 10.1038/s41598-020-80464-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 391

  ShuaiH.ChanJ. F. W.YuenT. T. T.YoonC.HuJ. C.WenL.et al. (2021). Emerging SARS-CoV-2 variants expand species tropism to murines. eBioMed.73:103643. doi: 10.1016/j.ebiom.2021.103643

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 392

  ShuklaN.RoelleS. M.SuzartV. G.BruchezA. M.MatreyekK. A. (2021). Mutants of human ACE2 differentially promote SARS-CoV and SARS-CoV-2 spike mediated infection. PLoS Pathog.17:e1009715. doi: 10.1371/journal.ppat.1009715

  • CrossRef
  • Google Scholar

• 393

  SiddiqueeK.HamptonJ.McAnallyD.MayL.SmithL. (2013). The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. Br. J. Pharmacol.168, 1104–1117. doi: 10.1111/j.1476-5381.2012.02192.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 394

  SiguretV.VoicuS.NeuwirthM.DelrueM.GayatE.StépanianA.et al. (2020). Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients?Thromb. Res.195, 74–76. doi: 10.1016/j.thromres.2020.07.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 395

  SilvaG. M.França-FalcãoM. S.CalzerraN. T. M.LuzM. S.GadelhaD. D. A.BalariniC. M.et al. (2020). Role of renin angiotensin system components in atherosclerosis: focus on Ang-II, ACE2, and Ang-1–7. Front. Physiol.11:1067. doi: 10.3389/fphys.2020.01067

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 396

  Simoes e SilvaA. C.SilveiraK. D.FerreiraA. J.TeixeiraM. M. (2013). ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br. J. Pharmacol.169, 477–492. doi: 10.1111/bph.12159

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 397

  SingerD.CamargoS. M. R. (2011). Collectrin and ACE2 in renal and intestinal amino acid transport. Channels5, 410–423. doi: 10.4161/chan.5.5.16470

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 398

  SingerD.CamargoS. M. R.RamadamT.SchäferM.MariottaL.HerzogB.et al. (2012). Defective intestinal amino acidabsorption in ACE2 null mice. Am. J. Physiol. Gastrointest. Liver Physiol.303, G686–G695. doi: 10.1152/ajpgi.00140.2012

  • CrossRef
  • Google Scholar

• 399

  SinghK. D.KarnikS. S. (2016). Angiotensin receptors: structure, function, signaling and clinical applications. J. Cell Signal.1:111. doi: 10.4172/jcs.1000111

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 400

  SkeggsL. T.Jr.KahnJ. R.ShumwayN. P. (1956). The preparation and function of the hypertensin-converting enzyme. J. Exp. Med.103, 295–299. doi: 10.1084/jem.103.3.295

  • CrossRef
  • Google Scholar

• 401

  SkidgelR. A.ErdosE. G. (1987). The broad substrate specificity of human angiotensin I converting enzyme. Clin. Exp. Hypertens. A9, 243–259. doi: 10.3109/10641968709164184

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 402

  SmadjaD. M.MentzerS.FontenayM.LaffanM. A.AckermannM.HelmsJ.et al. (2021). COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects. Angiogenesis24, 755–788. doi: 10.1007/s10456-021-09805-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 403

  SodhiC. P.Wohlford-LenaneC.YamaguchiY.PrindleT.FultonW. B.WangS.et al. (2017). Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. AJP Lung Cell. Mol. Physiol.314, L17–L31. doi: 10.1152/ajplung.00498.2016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 404

  SorokinaM.TeixeiraJ. M. C.Barrera-VilarmauS.PaschkleR.PapasotiriouI.RodriguesJ. P. L. M.et al. (2020). Structural models of human ACE2 variants with SARS-CoV-2 spike protein for structure-based drug design. Sci. Data7:309. doi: 10.1038/s41597-020-00652-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 405

  SpitlerK. M.WebbR. C. (2014). Endoplasmic reticulum stress contributes to aortic stiffening via proapoptotic and fibrotic signaling mechanisms. Hypertension63, e40–e45. doi: 10.1161/HYPERTENSIONAHA.113.02558

  • CrossRef
  • Google Scholar

• 406

  StawiskiEWDiwanjiDSuryamohanKGuptaR.FellouseFASathirapongsasutiJFet al. Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility. bioRxiv [Preprint] (2020). doi: 10.1101/2020.04.07.024752

  • CrossRef
  • Google Scholar

• 407

  StefelyJ. A.ChristensenB. B.GogakosT.Conne SullivanJ. K.MontgomeryG. G.BarrancoJ. P.et al. (2020). Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism. Am. J. Hematol.95, 1522–1530. doi: 10.1002/ajh.25979

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 408

  StrafellaC.CaputoV.TermineA.BaratiS.CaltagironeC.GiardinaE.et al. (2020). Investigation of genetic variations of IL6 and IL6r as potential prognostic and pharmacogenetics biomarkers: implications for covid-19 and neuroinflammatory disorders. Lifestyles10, 1–10. doi: 10.3390/life10120351

  • CrossRef
  • Google Scholar

• 409

  SuryamohanK.DiwanjiD.StawiskiE. W.GuptaR.MierschS.LiuJ.et al. (2021). Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2. Comm. Biol.4:475. doi: 10.1038/s42003-021-02030-3

  • CrossRef
  • Google Scholar

• 410

  TakayanagiT.KawaiT.ForresterS. J.ObamaT.TsujiT.FukudaY.et al. (2015). Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II. Hypertension65, 1349–1355. doi: 10.1161/HYPERTENSIONAHA.115.05344

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 411

  TanY. K.GohC.LeowA. S. T.TambyahP. A.AngA.YapE. S.et al. (2020). COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature. J. Thromb. Thrombolysis50, 587–595. doi: 10.1007/s11239-020-02228-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 412

  TangT.BidonM.JaimesJ. A.WhittakerG. R.DanielS. (2020). Coronavirus membrane fusion mechanism offers a potential target for antiviral development. Antivir. Res.178:104792. doi: 10.1016/j.antiviral.2020.104792

  • CrossRef
  • Google Scholar

• 413

  TayM. Z.PohC. M.ReniaL.MacAryP. A.NgL. F. P. (2020). The trinity of COVID19: immunity, inflammation and intervention. Nat. Rev. Immunol.20, 363–374. doi: 10.1038/s41577-020-0311-8

  • CrossRef
  • Google Scholar

• 414

  TereshchenkoL. G.JohnsonK.Khayyat-KholghiM.JohnsonB. (2022). Rate of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers use and the number of COVID-19–confirmed cases and deaths. Am. J. Cardiol.165, 101–108. doi: 10.1016/j.amjcard.2021.10.050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 415

  ThomasM. C.PickeringR. J.TsorotesD.KoitkaA.SheehyK.BernardiS.et al. (2010). Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse. Circ. Res.107, 888–897. doi: 10.1161/CIRCRESAHA.110.219279

  • CrossRef
  • Google Scholar

• 416

  TigerstedtR.BergmanP. G. (1898). Niere und kreislauf. Skand. Arch. Physiol.8, 223–271. doi: 10.1111/j.1748-1716.1898.tb00272.x

  • CrossRef
  • Google Scholar

• 417

  TignarelliC. J.IngrahamN. E.SparksM. A.ReilkoffR.BezdicekT.BensonB.et al. (2020). Antihypertensive drugs and risk of COVID-19?Lancet Respir. Med.8, e30–e31. doi: 10.1016/S2213-2600(20)30153-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 418

  TikellisC.PickeringR.TsorotesD.DuX. J.KiriazisH.Nguyen-HuuT. P.et al. (2012). Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes. Clin. Sci. (Lond.)123, 519–529. doi: 10.1042/CS20110668

  • CrossRef
  • Google Scholar

• 419

  TikellisC.ThomasM. C. (2012). Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int. J. Pept. Actions2012:256294. doi: 10.1155/2012/256294

  • CrossRef
  • Google Scholar

• 420

  TipnisS. R.HooperN. M.HydeR. (2000). A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J. Biol. Chem.275, 33238–33243. doi: 10.1074/jbc.M002615200

  • CrossRef
  • Google Scholar

• 421

  TongM.JiangY.XiaD.XiongY.ZhengQ.ChenF.et al. (2020). Elevated serum endothelial cell adhesion molecules expression in COVID-19 patients. J. Infect. Dis.222, 894–898. doi: 10.1093/infdis/jiaa349

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 422

  TowlerP.StakerB.PrasadS. G.MenonS.TangJ.ParsonsT.et al. (2004). ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J. Biol. Chem.279, 17996–18007. doi: 10.1074/jbc.M311191200

  • CrossRef
  • Google Scholar

• 423

  TukiainenT.VillaniA. C.YenA.RivasM. A.MarshallJ. L.SatijaR.et al. (2017). Landscape of X chromosome inactivation across human tissues. Nature550, 244–248. doi: 10.1038/nature24265

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 424

  TurnerA. J.HooperN. M. (2002). The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol. Sci.23, 177–183. doi: 10.1016/s0165-6147(00)01994-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 425

  UedaS.ElliottH. L.MortonJ. J.ConnellJ. M. (1995). Enhanced pressor response to angiotensin I in normotensive men with the deletion genotype (DD) for angiotensin-converting enzyme. Hypertension25, 1266–1269. doi: 10.1161/01.hyp.25.6.1266

  • CrossRef
  • Google Scholar

• 426

  UijlE.Mirabito ColafellaK. M.SunY.RenL.van VeghelR.GarreldsI. M.et al. (2019). Strong and sustained antihypertensive effect of small interfering RNA targeting liver angiotensinogen. Hypertension73, 1249–1257. doi: 10.1161/HYPERTENSIONAHA.119.12703

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 427

  VaduganathanM.VardenO.MichelT.McMurrayJ. J. V.PfefferM. A.SolomonS. D. (2020). Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19. N. Engl. J. Med.382, 1653–1659. doi: 10.1056/NEJMsr2005760

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 428

  VandestienneM.ZhangY.Santos-ZasI.Al-RifaiR.JoffreJ.GiraudA.et al. (2021). TREM-1 orchestrates angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm. J. Clin. Invest.131:e142468. doi: 10.1172/JCI142468

  • CrossRef
  • Google Scholar

• 429

  VaranatM.HaaseE. M.KayJ. G.ScannapiecoF. A. (2017). Activation of the TREM-1 pathway in human monocytes by periodontal pathogens and oral commensal bacteria. Mol Oral Microbiol32, 257–287. doi: 10.1111/omi.12169

  • CrossRef
  • Google Scholar

• 430

  VassiliouA. G.KeskinidouC.JahajE.GallosP.DimopoulouI.KotanidouA.et al. (2021). ICU admission levels of endothelial biomarkers as predictors of mortality in critically ill COVID-19 patients. Cells10:186. doi: 10.3390/cells10010186

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 431

  VelkoskaE.PatelS. K.BurrellL. M. (2016). Angiotensin converting enzyme 2 and diminazene: role in cardiovascular and blood pressure regulation. Curr. Opin. Nephrol. Hypertens.25, 384–395. doi: 10.1097/MNH.0000000000000254

  • CrossRef
  • Google Scholar

• 432

  VellosoL. A.FolliF.SunX. J.WhiteM. F.SaadM. J. A.KahnC. R. (1996). Cross-talk between the insulin and angiotensin signaling systems. Proc. Natl. Acad. Sci. U. S. A.93, 12490–12495. doi: 10.1073/pnas.93.22.12490

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 433

  VerdecchiaP.AngeliF.MazzottaG.GentileG.ReboldiG. (2008). The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. Vasc. Health Risk Manag.4, 971–981. doi: 10.2147/vhrm.s3215

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 434

  VerdecchiaP.CavalliniC.SpanevelloA.AngeliF. (2020). The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur. J. Intern. Med.76, 14–20. doi: 10.1016/j.ejim.2020.04.037

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 435

  VermaS.AbbasM.VermaS.KhanF. H.RazaS. T.SiddigiZ.et al. (2021). Impact of I/D polymorphism of angiotensin-converting enzyme 1 (ACE1) gene on the severity of COVID-19 patients. Infect. Genet. Evol.91:104801. doi: 10.1016/j.meegid.2021.104801

  • CrossRef
  • Google Scholar

• 436

  VermaA.XuK.DuT.ZhuP.LiangZ.LiaoS.et al. (2019). Expression of human ACE2 in lactobacillus and beneficial effects in diabetic retinopathy in mice. Mol. Ther. Methods Clin. Dev.14, 161–170. doi: 10.1016/j.omtm.2019.06.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 437

  VicenziM.Di CosolaR.RuscicaM.RattiA.RotaI.RotaF.et al. (2020). The liaison between respiratory failure and high blood pressure: evidence from COVID-19 patients. Eur. Respir. J.56:2001157. doi: 10.1183/13993003.01157-2020

  • CrossRef
  • Google Scholar

• 438

  VickersC.HalesP.KaushikV.DickL.GavinJ.TangJ.et al. (2002). Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J. Biol. Chem.277, 14838–14843. doi: 10.1074/jbc.M200581200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 439

  VitteJ.DialloA. B.BoumazaA.LopezA.MichelM.Allardet-ServentJ.et al. (2020). A granulocytic signature identifies COVID-19 and its severity. J. Infect. Dis.222, 1985–1996. doi: 10.1093/infdis/jiaa591

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 440

  Vuille-Dit-BilleR. N.CamargoS. M.EmmeneggerL.SasseT.KummerE.JandoJ.et al. (2015). Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids47, 693–705. doi: 10.1007/s00726-014-1889-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 441

  WacharapluesadeeS.TanC. W.ManeeornP.DuengkaeP.ZhuF.JoyjindaY.et al. (2021). Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in Southeast Asia. Nat. Commun.12:972. doi: 10.1038/s41467-021-21240-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 442

  WakaharaS.KonoshitaT.MizunoS.MotomuraM.AoyamaC.MakinoY.et al. (2007). Synergistic expression of angiotensin-converting enzyme (ACE) and ACE2 in human renal tissue and confounding effects of hypertension on the ACE to ACE2 ratio. Endocrinology148, 2453–2457. doi: 10.1210/en.2006-1287

  • CrossRef
  • Google Scholar

• 443

  WallsA. C.ParkY. J.TortoriciM. A.WallA.McGuireA. T.VeeslerD. (2020). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cells181, 281–292. doi: 10.1016/j.cell.2020.02.058

  • CrossRef
  • Google Scholar

• 444

  WangK.ChenW.ZhangZ.DengY.LianJ. Q.PengD.et al. (2020). CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. Signal Transduct. Target. Ther.5:283. doi: 10.1038/s41392-020-00426-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 445

  WangH.JiY.WuG.SunK.SunY.LiW.et al. (2015). L-tryptophan activates mammalian target of rapamycin and enhances expression of tight junction proteins in intestinal porcine epithelial cells. J. Nutr.145, 1156–1162. doi: 10.3945/jn.114.209817

  • CrossRef
  • Google Scholar

• 446

  WangC.JinR.ZhuX.YanJ.LiG. (2015). Function of CD147 in atherosclerosis and atherothrombosis. J. Cardiovasc. Transl. Res.8, 59–66. doi: 10.1007/s12265-015-9608-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 447

  WangF.LuX.PengK.ZhouL.LiC.WangW.et al. (2014). COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla. Am. J. Physiol. Ren. Physiol.307, F25–F32. doi: 10.1152/ajprenal.00548.2013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 448

  WangW.LuoL.LuH.ChenS.KangL.CuiF. (2015). Angiotensin-converting enzymes modulate aphid–plant interactions. Sci. Rep.5:8885. doi: 10.1038/srep08885

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 449

  WangC.WangS.LiD.WeiD. Q.ZhaoJ.WangJ. (2020). Human intestinal defensin 5 inhibits SARS-CoV-2 invasion by cloaking ACE2. Gastroenterology159, 1145–1147.e4. doi: 10.1053/j.gastro.2020.05.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 450

  WangQ.ZhangY.WuL.NiuS.SongC.ZhangZ.et al. (2020). Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cells181, 894–904.e9. doi: 10.1016/j.cell.2020.03.045

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 451

  WangM. Y.ZhaoR.GaoL. J.GaoX. F.WangD. P.CaoJ. M. (2020). SARS-CoV-2: structure, biology, and structure-based therapeutics development. Front. Cell. Infect. Microbiol.10:587269. doi: 10.3389/fcimb.2020.587269

  • CrossRef
  • Google Scholar

• 452

  WatanabeT.BarkerT. A.BerkB. C. (2005). Angiotensin II and the endothelium: diverse signals and effects. Hypertension45, 163–169. doi: 10.1161/01.HYP.0000153321.13792.b9

  • CrossRef
  • Google Scholar

• 453

  WeiC.ShanK. J.WangW.ZhangS.HuanQ.QianW. (2021). Evidence for a mouse origin of the SARS-CoV-2 omicron variant. J. Genet. Genom.48, 1111–1121. doi: 10.1016/j.jgg.2021.12.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 454

  WenzelJ.LampeJ.Müller-FielitzH.SchusterR.ZilleM.MüllerK.et al. (2021). The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nat. Neurosci.24, 1522–1533. doi: 10.1038/s41593-021-00926-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 455

  WicikZ.EyiletenC.JakubikD.SimoesS. N.MartinsD. C.Jr.PavaoR.et al. (2020). ACE2 interaction networks in COVID-19: a physiological framework for prediction of outcome in patients with cardiovascular risk factors. J. Clin. Med.9:3743. doi: 10.3390/jcm9113743

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 456

  WrightJ. M. (2000). Choosing a first-line drug in the management of elevated blood pressure: what is the evidence? 3: angiotensin-converting-enzyme inhibitors. CMAJ163, 293–296.

  • Google Scholar

• 457

  WuY.-H.LiJ.-Y.WangC.ZhangL.-M.QiaoH. (2017). The ACE2 G8790A polymorphism: involvement in type 2 diabetes mellitus combined with cerebral stroke. J. Clin. Lab. Anal.31:e22033. doi: 10.1002/jcla.22033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 458

  WysockiJ.Garcia-HalpinL.YeM.MaierC.SowersK.BurnsK. D.et al. (2013). Regulation of urinary ACE2 in diabetic mice. Am. J. Physiol. Physiol.305, F600–F611. doi: 10.1152/ajprenal.00600.2012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 459

  XiaoM.ZhangY.ZhangS.QinX.XiaP.CaoW.et al. (2020). Anti-phospholipid antibodies in critically ill patients with coronavirus disease 2019 (COVID-19). Arthritis Rheum.72, 1998–2004. doi: 10.1002/art.41425

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 460

  XiaoF.ZimpelmannJ.AgaybiS.GurleyS. B.PuenteL.BurnsK. D. (2014). Characterization of angiotensin-converting enzyme 2 ectodomain shedding from mouse proximal tubular cells. PLoS One9:e85958. doi: 10.1371/journal.pone.0085958

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 461

  XieX.ChenJ.WangX.ZhangF.LiuY. (2006). Age-and genderrelated difference of ACE2 expression in rat lung. Life Sci.78, 2166–2171. doi: 10.1016/j.lfs.2005.09.038

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 462

  XieY.XuE.BoweB.Al-AlyZ. (2022). Long-term cardiovascular outcomes of COVID-19. Nat. Med.28, 583–590. doi: 10.1038/s41591-022-01689-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 463

  XuQ.JensenD. D.PengH.FengY. (2016). The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure. Pharmacol. Ther.164, 126–134. doi: 10.1016/j.pharmthera.2016.04.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 464

  XuY.LiY. (2021). MicroRNA-28-3p inhibits angiotensin-converting enzyme 2 ectodomain shedding in 293T cells treated with the spike protein of severe acute respiratory syndrome coronavirus 2 by targeting a disintegrin and metalloproteinase 17. Int. J. Mol. Med.48:189. doi: 10.3892/ijmm.2021.5022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 465

  XuC.WangA.MarinM.HonnenW.RamasamyS.PorterE.et al. (2021). Human Defensins inhibit SARS-CoV-2 infection by blocking viral entry. Viruses13:1246. doi: 10.3390/v13071246

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 466

  XuH.ZhongL.DengJ.PengJ.DanH.ZengX.et al. (2020). High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int. J. Oral Sci.12:8. doi: 10.1038/s41368-020-0074-x

  • CrossRef
  • Google Scholar

• 467

  XueB.ZhangZ.RoncariC. F.GuoF.JohnsonA. K. (2012). Aldosterone acting through the central nervous system sensitizes angiotensin II-induced hypertension. Hypertension60, 1023–1030. doi: 10.1161/HYPERTENSIONAHA.112.196576

  • CrossRef
  • Google Scholar

• 468

  YamamotoN.NishidaN.YamamotoR.GojoboriT.ShimotohnoK.MizokamiM.et al. (2021). Angiotensin–converting enzyme (ACE) 1 gene polymorphism and phenotypic expression of COVID-19 symptoms. Gene12:1572. doi: 10.3390/genes12101572

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 469

  YanR.ZhangY.LiY.XiaL.GuoY.ZhouQ.et al. (2020). Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science367, 1444–1448. doi: 10.1126/science.abb2762

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 470

  YangJ. M.DongM.MengX.ZhaoY. X.YangX. Y.LiuX. L.et al. (2013). Angiotensin-(1-7) dose-dependently inhibits atherosclerotic lesion formation and enhances plaque stability by targeting vascular cells. Arteriosc. Thromb. Vascular Biol.33, 1978–1985. doi: 10.1161/ATVBAHA.113.301320

  • CrossRef
  • Google Scholar

• 471

  YangP.GuH.ZhaoZ.WangW.CaoB.LaiC.et al. (2014). Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci. Rep.4:7027. doi: 10.1038/srep07027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 472

  YangM.ZhaoJ.XingL.ShiL. (2015). The association between angiotensinconverting enzyme 2 polymorphisms and essential hypertension risk: a meta-analysis involving 14, 122 patients. J. Renin-Angiotensin-Aldosterone Syst.16, 1240–1244. doi: 10.1177/1470320314549221

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 473

  YenH. L.SitT. H. C.BrackmanC. J.ChukS. S. Y.GuH.TamK. W. S.et al. (2022). Transmission of SARS-CoV-2 delta variant (AY.127) from pet hamsters to humans leading to onward human-to-human transmission: a case study. Lancet399, 1070–1078. doi: 10.1016/S0140-6736(22)00326-9

  • CrossRef
  • Google Scholar

• 474

  YiL.GuY. H.WangX. L.AnL. Z.XieX. D.ShaoW.et al. (2006). Association of ACE, ACE2 and UTS2 polymorphisms with essential hypertension in Han and Dongxiang populations from North-Western China. J. Int. Med. Res.34, 272–283. doi: 10.1177/147323000603400306

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 475

  YimH. E.YooK. H. (2008). Renin-angiotensin system-considerations for hypertension and kidney. Electrol. Blood Press.6, 42–50. doi: 10.5049/EBP.2008.6.1.42

  • CrossRef
  • Google Scholar

• 476

  YuH. Q.SunB. Q.FanfZ. F.ZhaoJ. C.LiuX. Y.LiY. M.et al. (2020). Distinct features of SARS-CoV-2-specific IgA response in COVID-19 patients. Eur. Respir. J.56:2001526. doi: 10.1183/13993003.01526-2020

  • CrossRef
  • Google Scholar

• 477

  YuC.TangW.WangY.ShenQ.WangB.CaiC.et al. (2016). Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry. Cancer Lett.376, 268–277. doi: 10.1016/j.canlet.2016.04.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 478

  ZhangH.BakerA. (2017). Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Crit. Care21:305. doi: 10.1186/s13054-017-1882-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 479

  ZhangQ.BastardP.LiuZ.Le PenJ.Moncada-VelezM.ChenJ.et al. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science370:eabd4570. doi: 10.1126/science.abd4570

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 480

  ZhangJ.DongJ.MartinM.HeM.GongolB.MarinT. L.et al. (2018). AMP-activated protein kinase phosphorylation of ACE2 in endothelium mitigates pulmonary hypertension. Am. J. Respir. Crit. Care Med.198, 509–520. doi: 10.1164/rccm.201712-2570OC

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 481

  ZhangQ.GefterJ.SneddonW. B.MamonavaT.FriedmanP. A. (2021). ACE2 interaction with cytoplasmic PDZ protein enhances SARS-CoV-2 invasion. iScience24:102770. doi: 10.1016/j.isci.2021.102770

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 482

  ZhangS.LiuY.WangX.YangL.LiH.WangY.et al. (2020). SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J. Hematol. Oncol.13:120. doi: 10.1186/s13045-020-00954-7

  • CrossRef
  • Google Scholar

• 483

  ZhangX. J.QinJ. J.ChengX.ShenL.ZhaoY. C.YuanY.et al. (2020). In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. Cell Metab.32, 176–187. doi: 10.1016/j.cmet.2020.06.015.e4

  • CrossRef
  • Google Scholar

• 484

  ZhangC.ShenL.LeK. J.PanM. M.KongL. C.GuZ. C.et al. (2020). Incidence of venous thromboembolism in hospitalized coronavirus disease 2019 patients: a systematic review and meta-analysis. Front. Cardiovasc. Med.7:151. doi: 10.3389/fcvm.2020.00151

  • CrossRef
  • Google Scholar

• 485

  ZhangH.WadaJ.HidaK.TsuchiyamaY.HiragushiK.ShikataK.et al. (2001). Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J. Biol. Chem.276, 17132–17139. doi: 10.1074/jbc.M006723200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 486

  ZhangZ. Z.WangW.JinH. Y.ChenX.ChengY. W.XuY. L.et al. (2017). Apelin is a negative regulator of angiotensin II-mediated adverse myocardial remodeling and dysfunction. Hypertension70, 1165–1175. doi: 10.1161/HYPERTENSIONAHA.117.10156

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 487

  ZhangY.XiaoM.ZhangS.XiaP.CaoW.JiangW.et al. (2020). Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N. Engl. J. Med.382:e38. doi: 10.1056/NEJMc2007575

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 488

  ZhangL.ZhangY.QinX.JiangX.ZhangJ.MaoL.et al. (2022). Recombinant ACE2 protein protects against acute lung injury induced by SARS-CoV-2 spike RBD protein. Crit. Care26:171. doi: 10.1186/s13054-022-04034-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 489

  ZhangP.ZhuL.CaiJ.LeiF.QinJ. J.XieJ.et al. (2020). Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ. Res.126, 1671–1681. doi: 10.1161/CIRCRESAHA.120.317242

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 490

  ZhaoJ.YuanQ.WangH.LiuW.LiaoX.SuY.et al. (2020). Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin. Infect. Dis.71, 2027–2034. doi: 10.1093/cid/ciaa344

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 491

  ZhaoY.ZhaoZ.WangY.ZhouY.MaY.ZuoW. (2020). Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. Am. J. Respir. Crit. Care Med.202, 756–759. doi: 10.1164/rccm.202001-0179LE

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 492

  ZhengM.GaoY.WangG.SongG.LiuS.SunD.et al. (2020). Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell. Mol. Immunol.17, 533–535. doi: 10.1038/s41423-020-0402-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 493

  ZhouP.YangX. L.WangX. G.HuB.ZhangL.ZhangW.et al. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature579, 270–273. doi: 10.1038/s41586-020-2012-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 494

  ZhouF.YuT.DuR.FanG.LiuY.LiuZ.et al. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet395, 1054–1062. doi: 10.1016/S0140-6736(20)30566-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 495

  ZhuN.ZhangD.WangW.LiX.YangB.SongJ.et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med.382, 727–733. doi: 10.1056/NEJMoa2001017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 496

  ZhuangM. W.ChengY.ZhangJ.JiangX. M.WangL.DengJ.et al. (2020). Increasing host cellular receptor-angiotensin-converting enzyme 2 (ACE2) expression by coronavirus may facilitate 2019-nCoV (or SARS-CoV2) infection. J. Med. Virol.92, 2693–2701. doi: 10.1002/jmv.26139

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 497

  ZieglerC. G. K.AllonS. J.NyquistS. K.MbanoI. M.MiaoV. N.TzouanasC. N.et al. (2020). SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cells181, 1016–1035.e19. doi: 10.1016/j.cell.2020.04.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 498

  ZouX.ChenK.ZouJ.HanP.HaoJ.HanZ. (2020). Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front. Med.14, 185–192. doi: 10.1007/s11684-020-0754-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 499

  ZoufalyA.PoglitschM.AberleJ. H.HoeplerW.SeitzT.TraugottM.et al. (2020). Human recombinant soluble ACE2 in severe COVID-19. Lancet Respir. Med.8, 115–120. doi: 10.1016/S2213-2600(20)30418-5

  • CrossRef
  • Google Scholar

• 500

  ZuoY.YalavarthiS.ShiH.GockmanK.ZuoM.MadisonJ. A.et al. (2020). Neutrophil extracellular traps in COVID-19. JCI Insight5:e138999. doi: 10.1172/jci.insight.138999

  • Pubmed Abstract
  • CrossRef
  • Google Scholar