Edited by: Dan Meng, Fudan University, China
Reviewed by: Tao Zhuang, Fudan University, China; Yihua Bei, Shanghai University, China
This article was submitted to Cardiovascular Therapeutics, a section of the journal Frontiers in Cardiovascular Medicine
†These authors have contributed equally to this work and share first authorship
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Accumulating evidence has proved that non-coding RNAs (ncRNAs) play a critical role in the genetic programming and gene regulation of cardiovascular diseases (CVDs). Cardiovascular disease morbidity and mortality are rising and have become a primary public health issue that requires immediate resolution through effective intervention. Numerous studies have revealed that new types of cell death, such as pyroptosis, necroptosis, and ferroptosis, play critical cellular roles in CVD progression. It is worth noting that ncRNAs are critical novel regulators of cardiovascular risk factors and cell functions by mediating pyroptosis, necroptosis, and ferroptosis. Thus, ncRNAs can be regarded as promising therapeutic targets for treating and diagnosing cardiovascular diseases. Recently, there has been a surge of interest in the mediation of ncRNAs on three types of cell death in regulating tissue homeostasis and pathophysiological conditions in CVDs. Although our understanding of ncRNAs remains in its infancy, the studies reviewed here may provide important new insights into how ncRNAs interact with CVDs. This review summarizes what is known about the functions of ncRNAs in modulating cell death-associated CVDs and their role in CVDs, as well as their current limitations and future prospects.
Despite significant advances in prevention, diagnosis, and early intervention, cardiovascular diseases (CVDs) remain the leading cause of global mortality and a significant contributor to a decline in quality of life for many people (
The pathophysiology of CVDs is complicated (
ncRNA is a link that cannot be ignored in the occurrence and development of CVDs. ncRNAs account for 98–99% of the human genome and are involved in modulating the expression of genes encoding proteins (
Furthermore, ncRNAs play a role in the precise regulation of PCD. In the past few years, an increasing number of studies have identified that ncRNA has functional roles in regulating traditional PCD, such as apoptosis, necrosis, and autophagy (
Recently, newly discovered PCDs, such as necroptosis, pyroptosis, and ferroptosis, have been studied, with ample evidence indicating that PCD is a potential key factor in the CVD process (
This review summarizes the progress of the regulatory mechanisms of necroptosis, pyroptosis, and ferroptosis in CVDs and the role of ncRNAs, particularly circRNAs, lncRNAs, and miRNAs, in modulating PCD in CVDs. Identifying these cardiovascular disease-associated ncRNAs will help us understand how CVDs work and provide some new targets and implications for their prevention and treatment. Furthermore, we provide an update on recent developments and perspectives for the clinical and therapeutic use of ncRNAs on pyroptosis, necroptosis, and ferroptosis in CVDs, and their current limitations and prospects for future research.
Necroptosis is a type of necrosis controlled by death receptors (
The molecular signaling mechanisms and pathways of pyroptosis, necroptosis, and ferroptosis in cardiac cells. Necroptosis can be triggered by RIPK3 and RIPK1, which recruit MLKL to form the necrosome. The caspase-1 induced classical inflammasome pathway, caspase-4, caspase-5, and caspase-11 induced non-classical pathways, and caspase-3 and caspase-8 induced alternative pathways can trigger pyroptosis. Ferroptosis can be activated by iron accumulation and low levels of GSH-induced lipid peroxidation.
Necroptosis is involved in the pathogenesis of various CVDs, including AS, I/R injury, and MI.
In the early stage of AS, circulating monocytes enter the subintima to phagocytose ox-LDL through damaged vascular epithelial cells, turning them into foam cells. Subsequently, the expression of RIP3 and MLKL in foam cells is upregulated so that necroptosis is activated, manifesting as inflammation, ultimately boosting the development of AS (
When myocardial I/R injury occurs, necroptosis will also arise soon afterward by triggering the RIP1-RIP3-MLKL complex, which can exacerbate myocardial oxidative stress and aggravate I/R injury, simultaneously accompanied by an inflammatory response (
RIP3-mediated inflammation is instrumental to the pathogenesis of MI. This inflammatory response results in adverse ventricular remodeling after MI by promoting ROS production (
ncRNA manifests as a complete axis that connects the occurrence of PCD with the development of CVDs. In this axis, lncRNA and circRNA compete with target miRNA for the 3′UTR binding site of mRNA to play a negative role in regulating downstream mRNA expression. The activation of this axis can result in the release of tremendous inflammasome that induces the corresponding PCD-like necroptosis and promotes the process of various CVDs. In addition, lncRNA and circRNA can act as “ molecular sponges” to inhibit miRNA expression to participate in the gene expression modulation, thus influencing the development of CVDs.
miRNAs play critical roles in ischemia-reperfusion (I/R) injury (
Similarly, miRNAs play a role in myocardial infarction (MI) pathology. MI, also known as a heart attack, is most commonly caused by reduced or interrupted blood flow to a part of the heart, resulting in cardiac cell death. In addition, because the epicardial artery is important in feeding the heart muscle, a blood clot embedded in it is usually the primary cause of ischemic myocardium necrosis. However, it is now recognized that blood clot etiology is not required in all cases. The blood supply must match the oxygen demand of all living tissues, including the heart muscle. This is referred to as a supply–demand relationship. In the absence of blood clots, it is now known that if the heart rate is too high or the blood pressure drops, this imbalance in the ratio will damage the heart muscle (
miRNAs play an important role in atherosclerosis (AS). AS is an inflammatory disease of the arterial intima caused by lipids. The final clinical outcome is determined by balancing its pro-inflammatory and anti-inflammatory mechanisms. Macrophages are primarily responsible for the infiltration, modification, and uptake of intimal plasma-derived lipoproteins, resulting in the formation of lipid-filled foam cells and atherosclerotic lesions (
In other CVDs like myocardial necroptosis prompted by Se deficiency, Yang's study found that overexpression of miR-200a-5p rendered receptor-interacting serine/threonine kinase 3 (RIP3)-dependent necroptosis in cardiomyocytes and animal models by targeting gene ring finger protein 11 (RNF11) (
There have only been a few reports that lncRNA regulates necroptosis in CVDs. Previous research in I/R injury found that necrosis-related factor (NRF), a long non-coding RNA, regulated cardiomyocyte necrosis by targeting miR-873, which inhibited RIPK1/RIPK3 translation and suppressed RIPK1/RIPK3-mediated necroptosis in cardiomyocytes induced by I/R injury (
In general, what has been discussed thus far indicates that ncRNA plays an important role in CVDs by regulating necroptosis, as shown in
Non-coding RNAs regulate necroptosis in various type of CVDs.
Ischemia/reperfusion(I/R) | miR-24-3p | C57BL/6 mice cardiomyocytes | RIPK1 | Repression | ( |
miR-223-3p | Pre-miR-223 transgenic (TG) mouse cardiomyocytes | NLRP3/IKKα | Repression | ( |
|
miR-223-5p | pre-miR-223-knockout (KO) mouse cardiomyocytes | TNFR1/DR6 | Repression | ( |
|
Atherosclerosis (AS) | miR-210 | inflammatory bone marrow-derived macrophages | Decr1 | Induction | ( |
miR-383 | inflammatory bone marrow-derived macrophages | poly(ADP-ribose)-glycohydrolase (Parg) | Repression | ( |
|
Acute kidney injury | miR-223-3p | C57 BL/6 mice tubular cell | RIPK3 | Repression | ( |
has-miR-500a-3p | human tubular epithelial cells | MLKL | Repression | ( |
|
Se deficiency-induced myocardial necroptosis | miR-200a-5p | Se-deficient chicken cardiomyocytes | RNF11 | Induction | ( |
Myocardial infarction (MI) | miR-103 | Mice's heart tissue with isoprenaline-induced myocardial infarction | FADD | Induction | ( |
miR-155 | cardiomyocyte progenitor cells | RIPK1 | Repression | ( |
|
miR-325-3p | C57BL/6 mice cardiomyocytes | RIPK3 | Repression | ( |
|
Sepsis | miR-425-5p | C57BL/6 mice liver cell | RIPK1 | Repression | ( |
I/R injury | lncRNA NRF | neonatal mouse |
miR-873 | Induction | ( |
ncRNAs are involved in CVDs by influencing the occurrence of necroptosis and ferroptosis.
The activation of RIPK1, RIPK3, and MLKL is core links in the necroptosis pathway, which are associated with their phosphorylation. Accordingly, phosphorylation of RIP1, RIP3, and MLKL can be used as the hallmarks of the induction of necroptosis
Pyroptosis, also known as a form of distinct programmed cell death; compared to other forms (e.g., apoptosis and autophagic cell death), its morphology is unique that is influenced by inflammatory caspases (
Pyroptosis plays a critical role in the pathophysiology of different CVDs.
In I/R injury, although ischemia itself can damage the heart muscle, most of the myocardial infarctions stem from injury during reperfusion after a transient period of coronary artery occlusion. The occurrence of pyroptosis results from the activation of caspase and the cleavage of GSDMD induced by inflammasomes. This active fragment creates large pores in the cell membrane to destroy the myocardiocyte, thus aggravating myocardial injury (
Vascular endothelial cells (VEC) damage is indispensable to As lesions. The caspase-1 inflammasome pathway can upregulate pyroptosis-related proteins and ultimately trigger VEC pyroptosis, which brings about the loss of endothelium integrity and the increase of vascular permeability, thus promoting As development (
The inflammatory response is involved in the development of cardiac hypertrophy (CH) and heart failure (HF). NLRP3 inflammasome components have been discovered in cardiomyocytes, resulting in pyroptosis. This process eventually causes cardiomyocyte proliferation and cytoskeletal remodeling, which can exacerbate the impairment of cardiac function and promote the development of CH and HF (
Cardiac fibrosis, one of the primary pathogenesis of diabetic cardiomyopathy (DC), plays a significant role in the process of DC induced by cardiac fibroblasts (CFs) (
MicroRNAs (miRNAs) carry out a variety of cellular functions (
NLRP3 plays an important role in the development of I/R injury, acting as a molecular platform and activating caspase-1 and cleaving pro-IL-1β, pro-IL-18, and GSDMD (
SIRT1 is another important pyroptosis molecule in I/R injury. SIRT1/PGC-1α/Nrf2 signaling has been shown to mediate oxidative stress, which is important in myocardial I/R injury (
Furthermore, FOXO3 is a key player in I/R injury, which increases oxidative damage and decreases myocardial function (
Other molecules, such as CRISPLD2, RP105, and MCL-1, also play protective roles in cardiomyocyte pyroptosis. By directly targeting CRISPLD2 and regulating cardiomyocyte pyroptosis, miR-424 promoted cardiac I/R injury (
In AS, miR-125a-5p mediated oxLDL-induced pyroptosis in vascular endothelial cells (VECs) by downregulating TET2 and increasing NF-κB activation, which activated NLRP3 and caspase-1, contributing to VECs and AS pyroptosis (
miRNAs play an important role in cardiac hypertrophy (CH) and heart failure (HF). CH causes changes in cardiomyocytes such as calcium processing, metabolism, and gene expression, as well as cell death (apoptosis and autophagy), extracellular matrix (ECM) changes (fibrosis), and angiogenesis. HF is a crippling condition in which the heart fails to supply oxygen to the body. The heart initially responds to additional stress or heart damage in a compensatory manner, increasing its volume and mass to normalize wall stress and cardiovascular function at rest. Pathological CH refers to the typical enlargement of the heart (
Furthermore, Fan et al. discovered that miR-599 inhibited pyroptosis caused by H2O2 by downregulating the expression of ASC as well as the downstream inflammatory factors IL-18 and IL-1β in oxidative stress-induced cardiac injury (
Diabetic cardiomyopathy (DC), another common type of CVD, is defined as cardiac dysfunction in diabetic patients who do not have other cardiovascular diseases (
Recent research in SIMD found that the lncRNA ZFAS1, which is activated by the transcription factor SP1, reduces the expression of miR-590-3p, which regulates the AMPK/mTOR signal pathway, influencing NLRP3-dependent pyroptosis of cardiomyocytes and promoting SIMD (
Similar to miRNAs, lncRNAs function in the regulation of pyroptosis in CVDs (
Furthermore, in AS, intragastric administration of melatonin reduced the expression of pyroptosis-related genes, such as cleaved-caspase-1, ASC, NLRP3, GSDMD-N termini, NF-κB/GSDMD cleaved-caspase-1, IL-1β, and IL-18, which significantly reduced atherosclerotic plaques in mouse aortas fed a high-fat diet
Yang et al. also reported in DC that lncRNA sponged miR-214-3p by competing for binding sites and regulating gene expression. Silencing the lncRNA Kcnq1ot1 reduced pyroptosis and fibrosis in diabetic cardiomyopathy by targeting miR-214, which influenced the expression level of its downstream proteins (e.g., caspase-1, TGF-β1) (
So far, only a few circRNAs have been proven to play a critical role in CVDs. Yang et al. discovered in DC that the caspase-1-associated circRNA (CACR), hsa_circ_0076631, functioned as a ceRNA, sequestering miR-214-3p and thus alleviating its suppressive effect on caspase-1 expression. Pyroptosis in cardiomyocytes treated with high glucose could thus be significantly reduced (
In summary, ncRNAs are demonstrated to play an important role in CVDs through the regulation of pyroptosis, as shown in
Non-coding RNAs regulate pyroptosis in various types of CVDs.
I/R injury |
miR-1 | H9c2 myocardial cells | PIK3R1 | Induction | ( |
miR-29a | H9c2 myocardial cells | SIRT1 | Induction | ( |
|
miR-29b | neonatal rat |
FoxO3a | Induction | ( |
|
Exo-miR-29a | neonatal mouse |
Mcl-1 | Induction | ( |
|
hucMSC exo-miR-100-5p | AC16 cells | FoxO3 | Repression | ( |
|
miR-132 | H9c2 myocardial cells | SIRT1 | Induction | ( |
|
miR-135b | neonatal mice |
NLRP3/caspase-1 | Repression | ( |
|
M2 exo-miR-148a | neonatal rat |
TXNIP | Repression | ( |
|
miR-149 | H9c2 myocardial cells | FoxO3 | Induction | ( |
|
M2 exo-miR-320 | neonatal rat |
NLPR3 | Repression | ( |
|
miR-383 | rat cardiomyocyte | RP105 | Induction | ( |
|
miR-424 | H9c2 myocardial cells | CRISPLD2 | Induction | ( |
|
miR-703 | mouse cardiomyocytes | NLRP3/caspase-1 | Repression | ( |
|
Atherosclerosis | miR-30c-5p | human aortic |
FoxO3 | Repression | ( |
miR-125-5p | vascular endothelial cells | TET2 | Induction | ( |
|
miR-181-5p | human umbilical vein |
STAT3 | Repression | ( |
|
miR-200a | RAW264.7 cells | Nrf2 | Repression | ( |
|
Diabetic cardiomyopathy | miR-9 | human ventricular cardiomyocytes | ELAV1 | Repression | ( |
miR-21-3p | neonatal rat |
AR | Induction | ( |
|
miR-30d | neonatal rat |
FoxO3a | Induction | ( |
|
Uremic cardiomyopathy | exo-miR-155 | C57BL/6 cardiomyocytes | FoxO3a | Induction | ( |
Cardiac hypertrophy and heart failure | miR-133a-3p | human cardiomyocyte | IKKε | Repression | ( |
miR-351 | TAC mice cardiomyocyte | MLK3 | Repression | ( |
|
I/R injury |
hMSCs exo-lncRNA KLF3-AS1 | H9c2 myocardial cells | miR-138-5p | Repression | ( |
lncRNA H19 | H9c2 myocardial cells | CYP1B1 | Repression | ( |
|
Diabetic cardiomyopathy | lncRNA Kcnq1ot1 | Cardiac fibroblasts | miR-214-3p | Induction | ( |
lncRNA GAS5 | HL-1 | miR-34b-3p | Repression | ( |
|
Sepsis-induced cardiac dysfunction | lncRNA ZFAS1 | neonatal mice |
miR-590-3p | Induction | ( |
Atherosclerosis | lncRNA MEG3 | human aortic |
miR-223 | Induction | ( |
lncRNA MALAT1 | EA.hy926 cells | miR-22 | Induction | ( |
|
lncRNA MALAT1 | bone-marrow-derived |
miR-23c | Induction | ( |
|
lncRNA NEXN-AS1 | human vascular |
NEXN | Repression | ( |
|
lncRNA H19 | Raw264.7 cells | miR-130b | Induction | ( |
|
MI | circHelz | neonatal mouse ventricular cardiomyocytes | miR-133a-3p | Induction | ( |
Diabetic cardiomyopathy | hsa_circ_0076631 | AC16 cells | miR-214-3p | Induction | ( |
Non-coding RNAs play an essential role in CVDs through pyroptosis regulation. AS, atherosclerosis; CH, cardiac hypertrophy; DC, diabetic cardiomyopathy; HF, heart failure; I/R, ischemia-reperfusion; SIMD, sepsis-induced myocardial dysfunction; UC: uremic cardiomyopathy.
The mechanism of pyroptosis involves three major signaling pathways, all activating downstream GSDMD and E, which leads to the release of IL-1 and IL-18. Accordingly, corresponding markers can be employed for detecting pyroptosis, such as the cleavage of GSDM D and E, release of IL-1β and −18, or caspase-1, −3, −4, −5, −8, and −11. Immunological techniques like western blotting can be applied as the most effective methods to detect or monitor pyroptosis owing to little involvement in transcription and translation during the modulation of pyroptosis (
Ferroptosis is an oxidation iron-dependent cell death that differs from apoptosis, necroptosis, pyroptosis, and other types of cell death (
Ferroptosis is also considered a crucial part of the pathophysiology of diverse CVDs.
During myocardial I/R injury, large amounts of degraded ferritin lead to the release of tremendous amount of iron into the coronary arteries. Subsequently, excessive iron in coronary arteries can impair cardiac function and exacerbate myocardial damage (
In the early and middle stages of MI, the expression of Gpx4 is inhibited, but the content of ROS increases, thus causing the ferroptosis of myocardial cells and the deterioration of cardiac function (
Iron homeostasis plays an indispensable role in maintaining myocardial function. Either iron deficiency or iron overload can worsen cardiac function in HF (
Song et al. reported in MI that exosomes derived from HUCB-MSCs could carry miR-23a-3p to protect cardiomyocytes against I/R-induced ferroptosis by downregulating divalent metal transporter 1 (DMT1) expression, thereby attenuating myocardial injury in AMI mice (
miR-214 has been reported to mediate iron translocation into cells in I/R injury by modulating transferrin receptor 1 protein (TFR1)
Zheng et al. discovered in HF that miR-224-5p could bind to the 3′UTR region of ferritin heavy chain 1 (FTH1) and functioned as a downstream target of circSnx12, which regulated miR-224-5p expression. Furthermore, silencing circSnx12 or overexpression of miR-224-5p could cause cardiac cell death by lowering FTH1 expression and directly regulating iron overload in cardiomyocytes (
As indicated above, ncRNAs are involved in CVDs by influencing the occurrence of ferroptosis, as shown in
Non-coding RNAs regulate ferroptosis in various types of CVDs.
Myocardial infarction (MI) | miR-23a-3p | neonatal mouse ventricular cardiomyocytes | DMT1 | Repression | ( |
miR-30d | H9c2 myocardial cells | ATG5 | Repression | ( |
|
Brain ischemia/reperfusion (I/R) | lncRNA PVT1 | C57BL/6 mice | miR-214 | Induction | ( |
Heart failure | circSnx12 | C57/BL6J mice cardiomyocytes | miR-224-5p | Repression | ( |
Ferroptosis is driven by the lethal accumulation of lipid peroxides in plasma membranes. Therefore, the determination of lipid peroxide level plays a key role in analyzing ferroptosis in biological samples. Recently, a newly discovered technique using BODIPY-C11 probe and flow cytometry to detect ferroptosis has been developed, which can assay cellular lipid peroxide levels in live cells with hypersensitivity and high accuracy (
Many ncRNAs have been identified as drug targets for treating CVDs in recent years, indicating the great potential of using ncRNAs as therapeutic targets in CVDs by influencing the manner of cell death. Recently, we found that piperine treatment can attenuate pyroptosis
Significant progress has been made in the field of ncRNA over the last few decades, particularly in terms of its nature, structure, and function. Part of the research findings has recently been successfully implemented in clinical applications. Except as a therapeutic target, one of its most useful applications in CVDs is as a biomarker. For instance, a study verified that lncRNA MALAT1 could serve as biomarkers with independent predictive properties for diagnosing, severity, and prognosis of patients with sepsis (
When compared to traditional biomarkers, ncRNAs have four distinct advantages as follows: (1) abnormal ncRNA expression is linked to the onset and progression of diseases. (2) ncRNA expression is found in cells, tissues, and organs and has high sensitivity and specificity for diagnosing certain diseases. (3) Furthermore, due to their ability to secrete into blood compartments and other body fluids, ncRNAs are simple to acquire and detect. (4) Finally, ncRNAs are relatively stable and capable of transmitting signals locally or over long distances due to exosome transport (
However, several huge challenges must be overcome before the clinical applications of ncRNAs in necroptosis, pyroptosis, and ferroptosis of CVDs: (1) low expression in body fluids: First, the relative abundance of specific lncRNAs may pose a problem. Because, despite the fact that ncRNAs are present in both peripheral blood and whole blood samples, most peripheral blood miRNAs may originate primarily from well-vascularized tissues (
In recent years, with the rapid development of quantification and standardization methodologies, the prevalence of ncRNAs as biomarkers has increased due to their disease specificity, accessibility, stability, and other distinguishing features, making ncRNAs valuable as biomarkers (
CVDs are the leading cause of death from nearly all diseases worldwide. Cell death has long been recognized as necessary for our tissues and bodies to maintain their typical morphological character and physiological function, but it has recently been identified as the primary cause of clinical diseases and severe pathological injuries. Recently, it has been reported that new types of PCD, such as pyroptosis, necroptosis, and ferroptosis, play a different role in the progression of CVDs. In this review, we summarized and analyzed the pathway of ncRNAs involved in necroptosis, pyroptosis, and ferroptosis and their impact on CVD pathogenesis, as shown in
PY and JZ: conceptualization, methodology, funding acquisition, and project administration. YC and YZ: writing original draft and formal analysis. ZL: visualization and supervision. PX: software and investigation. AS and XC: data curation, validation, writing—review and editing and resources. All authors contributed to the article and approved the submitted version.
This study was supported by the Natural Science Foundation in Jiangxi Province, China (Grant Nos. 202002BAB216022, 20192ACBL21037, and 202004BCJL23049), the National Natural Science Foundation of China (Nos. 82160371 and 82100869), and National Clinical Research Center for Geriatrics-JiangXi Branch Center (2021ZDG02001).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The graphical abstracts were created with BioRender software (