Oxidative stress-mediated changes promoted the development of cardiovascular disease (Massaeli and Pierce, 1995). It was found that RBP4 induces mitochondrial dysfunction and apoptosis, which in turn promotes vascular oxidative stress. RBP4 impaired mitochondrial number and integrity and reduced membrane potential by inducing reactive oxygen species (ROS) in mitochondria, and increased ROS and decreased ATP production affected normal endothelial cell. Increased cytochrome C release from mitochondria, increased Bax (pro-apoptotic protein) and decreased Bcl-2 were observed in arteries from RBP4 overexpressing (RBP4-Tg) mice, suggesting that RBP4 increased apoptosis of endothelial cell (Wang et al., 2015).

Chronic vascular inflammation plays an important role in the development of atherosclerosis, and vascular dysfunction promotes plaque initiation and progression (Endemann and Schiffrin, 2004). RBP4 may be involved in the development of cardiovascular disease by inducing an inflammatory response. Norseen et al. (2012) found that RBP4 induced macrophage pro-inflammatory cytokine secretion and expression through activation of C-Jun N-terminal protein kinase (JNK) and Toll-like receptor 4 (TLR4)-dependent signaling pathways (Figure 1). Similarly, RBP4 was found to mediate vascular endothelial cell inflammatory responses via NADPH oxidase and NF-κB-dependent pathways (Farjo et al., 2012). In addition to endothelial cells, RBP4 also increases the proliferation of vascular smooth muscle cells through MAPK pathway and increases the risk of cardiovascular diseases (Li et al., 2015). the receptor and signaling pathways by which RBP4 acts with endothelial cells and VSMCs deserve to be explored in further studies, which may contribute to the understanding of the RBP4 and cardiovascular disease linkage.

Hypertension is primarily a disease that results from genetic and environmental interactions, and its prevalence in the population is increasing year by year. It was found that blood RBP4 levels were significantly elevated in patients with untreated essential hypertension (Solini et al., 2009; Zachariah et al., 2016; Li et al., 2019) and significantly correlated with left ventricular diastolic function (Porcar-Almela et al., 2015; Li et al., 2019). RBP4 may be related to the left ventricular hypertrophy, and carotid intra-medial membrane thickness (IMT), suggesting that RBP4 may serve as a marker of vascular injury in hypertensive patients at early stage (Mansouri et al., 2012; Kraus et al., 2015). Significantly elevated levels of RBP4 were also found in patients with prehypertension, and RBP4 was independently associated with elevated diastolic and systolic blood pressure (Zhang et al., 2017). Insulin resistance (IR) has recently been suggested as a common pathophysiological basis for the development of type 2 diabetes and hypertension. Sasaki et al. (2020) found that the prevalence of hypertension increased with the degree of impaired glucose metabolism and elevated RBP4 may be involved in the development of hypertension by inducing IR. The mechanism of RBP4 in hypertension has not been clearly elucidated. Chiba et al. (2010) found that the binding of RBP4 to retinol activated inflammatory response that induced atherosclerosis, decreased vascular compliance and thus raised blood pressure. The correlation between RBP4 and arterial stiffness was also confirmed (Chondrou et al., 2020). It was found that blood pressure was reduced in RBP4 knockout (RBP-KO) mice and increased in RBP4 overexpressing (RBP-Tg) mice, while RBP-KO mice were protected from Ang-II-induced hypertension, confirming the presence of RBP4 as a risk factor in the development of hypertension (Kraus et al., 2015). The effect of RBP4 on blood pressure may be partly attributed to its effect on vascular endothelial function, as elevated RBP4 attenuates eNOS Ser1177 phosphorylation, which in turn attenuates the endothelium-dependent vasodilatory effect mediated by nitric oxide (Kraus et al., 2015; Figure 1).

Although the underlying mechanisms need to be further explored, more and more studies are now showing the close correlation between RBP4 and hypertension, and the monitoring of RBP4 may be a valuable indicator in determining early ventricular diastolic insufficiency and changes in vascular compliance in hypertensive patients. RBP4 may be a potential targeted molecule for preventing the progression of prehypertension and delaying ventricular remodeling.

Terminal B-type natriuretic peptide (NT-proBNP) is now known to be widely used as a diagnostic indicator of heart failure. Previous studies in elderly patients hospitalized with heart failure have shown that RBP4 did not correlate with NT-proBNP, and that changes of blood RBP4 levels are more likely attributable to the deterioration of renal function in patients with advanced heart failure, resulting in the accumulation of circulating adipokines (Majerczyk et al., 2018). It was found that alterations in RBP4 in patients with type 2 diabetes were also attributed to the changes of renal function (Henze et al., 2008). It seems to be no relationship between RBP4 and diagnosing of heart failure. But a subsequent prospective cohort study showed that in elderly patients with chronic heart failure, blood RBP4 levels were negatively correlated with left ventricular ejection fraction (LVEF) and positively correlated with NT-proBNP, and that serum RBP4 levels increased with decreasing cardiac function (Li et al., 2020; Table 1), In addition, the results of a 60-month follow-up suggested that blood RBP4 levels were positively correlated with adverse events in patients with chronic heart failure. The finding that RBP4 levels were positively correlated with left ventricular mass index (LVMI) and left atrial internal diameter (LAD) also suggests that RBP4 plays a role in the process of cardiac remodeling (von Jeinsen et al., 2018). The blood RBP4 levels in patients with advanced heart failure can be improved by implantation of a ventricular assist device (Chavarria et al., 2012). So RBP4 is a valuable diagnostic indicator of heart failure, and may be involved in the pathogenesis and development of heart failure.

Retinol-binding protein 4 is involved in the pathological process of heart failure through a variety of mechanisms. The elevation of RBP4 in patients with advanced heart failure may result from upregulation of RBP4 mRNA expression by IL-8 (Bobbert et al., 2009). In addition, RBP4 was found to cause cardiomyocyte hypertrophy, which may mediate a vicious cycle between insulin resistance and heart failure (Gao et al., 2016; von Jeinsen et al., 2018). RBP4 increased cell size, enhanced protein synthesis, and elevated the expression of hypertrophic markers including Anp, Bnp, and Myh7 in primary cardiomyocytes, but inhibition or knockdown of the TLR4/MyD88 pathway attenuated inflammatory and hypertrophic responses to RBP4 stimulation (Gao et al., 2016; Figure 1). Angiotensin II (Ang-II) also increases the expression of RBP4 in adipocytes, and the use of Ang-II receptor antagonists may eliminate this effect, which may explain another mechanism of the renin-angiotensin-aldosterone system (RASS) in exacerbating the deterioration of cardiac function (Gao et al., 2016). This needs to be explored in more clinical studies in the future.

Retinol-binding protein 4 levels in patients with coronary artery disease were found to be significantly higher than in the non-coronary artery disease (CAD) group (Ingelsson and Lind, 2009; Li et al., 2014; Liu et al., 2019) and positively correlated with the number of diseased vessels (Cubedo et al., 2014; Liu et al., 2015; Wessel et al., 2019), some clinical results have shown that serum RBP4 levels are reduced in patients with acute myocardial infarction, in male patients with familial hypercholesterolemia, a reduction in RBP4 has shown predictive significance for the possibility of ischemic events in the next 2 years, suggesting that RBP4 may be involved in the AMI (Cubedo et al., 2014). Similarly, Liu et al. (2015) found that patients with CAD with higher RBP4 had a concomitant increase in acute coronary syndrome (ACS) events in a 3-year follow-up (Table 1).

Previously, Mallat found that RBP did not provide additional predictive value compared to traditional risk factors in normal subjects (Mallat et al., 2009). But in a 16-year prospective case-control study (Sun et al., 2013), both full-length and total RBP4 levels were found to be strongly associated with the risk of coronary heart disease in women, with this association diminishing over time. Full-length RBP4 may exist as the most biologically active isoform of RBP4. In addition, increased values of both RBP4 and lipoprotein conjugate index (LCI) were found to be independent risk factors for ACS, and the combined test results of LCI and RBP4 values may serve as a potential indicator for the diagnosis of ACS (Wessel et al., 2019). RBP4 gene polymorphism was also found to be closely associated with coronary artery disease (Wan et al., 2014). Liu et al. (2017) found that RBP4 was localized in macrophage-rich foam cells, that RBP4 promotes the formation of macrophage-derived foam cells by activating the c-Src-JNK-STAT1 signaling pathway, which in turn upregulates CD36 expression and cholesterol uptake, and that RBP4 concentration is negatively correlated with carotid intima and plaque echogenicity (Stakhneva et al., 2020; Figure 1 and Table 1). The results suggested that RBP4 was involved in the progression of atherosclerosis. In conclusion, RBP4 involved in the pathophysiological process of coronary heart disease, as a risk factor, has shown valuable in predictor of coronary complexity and the occurrence of adverse cardiovascular events in patients with CAD. RBP4 is expected to be a new biological indicator of coronary heart disease, and a clinical risk factor of coronary heart disease.

Cardiac amyloidosis (CA) is an accumulation of insoluble fibrous deposits composed of abnormally folded protein molecules in the myocardial interstitial, which mainly manifests clinically as cardiac insufficiency, various arrhythmias, and angina pectoris, among which the transthyretin amyloidosis (ATTR) type is more common in clinical work. It was found that blood RBP4 levels in patients with transthyretin amyloidosis were significantly lower than in controls (Arvanitis et al., 2017a,b). Chan et al. (2017) further found that RBP4 was significantly decreased in mutant myocardial amyloidosis (ATTRm) compared to controls, but not in wild-type myocardial amyloidosis (ATTRwt) by using blood proteomics analysis. The reduced level of serum TTR was closely correlated with the reduced level of RBP4 (Suhr et al., 2015). The lower levels of RBP4 paralleled to serum TTR levels, which may be related to the fact that TTR acts as a transporter protein to bind the RBP4-retinol complex and thus reduces renal excretion of RBP4 (Hamilton and Benson, 2001; Table 1).

Retinol-binding protein 4 has been found to have anti-amyloidogenic properties, and the decrease of RBP4 alleviate the formation of the RBP4-retinol complex and attenuates its role in stabilizing the TTR tetrameric structure (White and Kelly, 2001; Santos et al., 2016). In vitro assays have shown that the RBP-retinol complex (holoRBP) inhibits the rate of amyloid fibril formation in a concentration-dependent manner (White and Kelly, 2001). holoRBP at physiological concentrations slowed down the rate of TTR breakdown approximately sixfold compared to TTR breakdown alone (Hyung et al., 2010). RBP4 concentrations higher than or equal to 50 μg/mL were found to be up to 100% sensitive for the diagnosis of ATTRV122I amyloidosis, although its specificity decreased to 38%, suggesting that RBP4 could provide 100% negative predictive value when used to rule out ATTRV122I amyloidosis (Arvanitis et al., 2017a; Table 1). The diagnostic and predictive value of RBP4 in ATTR amyloidosis needs to be confirmed in larger and more pathologically diverse cohort studies.