The Biological Mechanisms and Clinical Roles of RNA-Binding Proteins in Cardiovascular Diseases

Abstract

RNA-binding proteins (RBPs) have pivotal roles in cardiovascular biology, influencing various molecular mechanisms underlying cardiovascular diseases (CVDs). This review explores the significant roles of RBPs, focusing on their regulation of RNA alternative splicing, polyadenylation, and RNA editing, and their impact on CVD pathogenesis. For instance, RBPs are crucial in myocardial injury, contributing to disease progression and repair mechanisms. This review systematically analyzes the roles of RBPs in myocardial injury, arrhythmias, myocardial infarction, and heart failure, revealing intricate interactions that influence disease outcomes. Furthermore, the potential of RBPs as therapeutic targets for cardiovascular dysfunction is explored, highlighting the advances in drug development and clinical research. This review also discusses the emerging role of RBPs as biomarkers for cardiovascular diseases, offering insights into their diagnostic and prognostic potential. Despite significant progress, current research faces several limitations, which are critically examined. Finally, this review identifies the major challenges and outlines future research directions to advance the understanding and application of RBPs in cardiovascular medicine.

Keywords: RNA alternative splicing; RNA-binding proteins (RBPs); biomarkers; cardiovascular diseases (CVDs); myocardial injury; therapeutic targets.

Figure 1

RNA-binding proteins (RBPs) have a crucial role in cardiovascular biology. MBNL1: muscleblind-like 1, a crucial regulator of cardiomyocyte maturity, controls the transition between proliferative and hypertrophic growth, and is essential for stabilizing gene expression networks that maintain the differentiated state of adult heart cells. PCBP2: Poly(rC)-binding protein 2, a key post-transcriptional and translational regulator, plays a crucial role in inhibiting cardiac hypertrophy by stabilizing mRNA and repressing the expression of target genes such as GPR56 in heart tissue. GPR56: G protein-coupled receptor 56, a critical transmembrane receptor, is involved in the regulation of cell–cell interactions, myelin sheath formation, and the development of the central nervous and hematopoietic systems. GPR56 plays an essential role in inhibiting cardiac hypertrophy by modulating gene expression and interacting with various ligands.

Figure 2

RNA-Binding proteins affect cardiovascular diseases through polyadenylation. In diabetic hearts, the RNA-binding protein CUG-BP (CELF1) is upregulated, playing a crucial role in key processes like alternative splicing and polyadenylation, the latter involving cleavage and poly(A) tail addition to mRNA transcripts. CUG-BP (CELF1): CUGBP elav-like family member 1, a multifunctional RNA-binding protein, is crucial for the regulation of mRNA splicing, stability, and translation in various tissues, including the myocardium, playing an essential role in myofibril organization, cell proliferation, and morphogenesis during cardiac development.

Figure 3

RNA-binding proteins (RBPs) utilize RNA-binding domains to regulate gene expression through various post-transcriptional mechanisms. (a) the expression of critical splicing factors such as SF1, ZRSR2, SRSF4, and SRSF5 is downregulated in dysfunctional cardiomyocytes. (b) CIRP binding to heart RNAs boosts KCND2 and KCND3 translation, enhancing potassium channel activity. (c) RBFOX2 downregulation causes heart issues, leading to failure. (d) Variable splicing links to various heart diseases. (e) S100A11, Anxa2, and JunB regulate splicing and affect muscle activity with calcium. SF1: Splicing Factor 1, a key RNA splicing factor, plays a crucial role in maintaining cardiac function by regulating mRNA splicing, and its downregulation in dysfunctional cardiomyocytes contributes to impaired cardiac function and disease progression. SF1 is essential for the proper expression of cardiac genes and the maintenance of cellular homeostasis, influencing processes such as cell survival, differentiation, and response to stress. ZRSR2: Zinc finger CCCH-type, RNA-binding motif and serine/arginine-rich 2, a critical RNA splicing factor, plays an essential role in the regulation of mRNA splicing and is crucial for maintaining cardiac function. Its downregulation in dysfunctional cardiomyocytes impairs cardiac reprogramming and enhances the conversion of cardiac fibroblasts to induced cardiomyocytes (iCMs), highlighting its importance in cellular differentiation and heart disease progression. SRSF4: Serine/arginine-rich splicing factor 4, a crucial RNA-binding protein involved in the regulation of alternative splicing, plays an essential role in maintaining cardiac function. Its downregulation in dysfunctional cardiomyocytes leads to cardiac hypertrophy, diastolic dysfunction, and abnormal repolarization, highlighting its significance in the progression of heart disease. SRSF5: Serine/arginine-rich splicing factor 5, a glucose-inducible RNA-binding protein, plays a crucial role in heart development by regulating the alternative splicing of key cardiac structural genes. CIRP: Cold-inducible RNA-binding protein, a crucial regulator of RNA stability and translation, plays a vital role in maintaining cardiac bioelectric activity by facilitating the translation of key potassium channel subunits, KCND2 and KCND3. KCND2: Potassium voltage-gated channel subfamily D member 2, a crucial component of the transient outward potassium current (I_TO) in the heart, plays a vital role in cardiac repolarization and electrical stability. KCND3: Potassium voltage-gated channel subfamily D member 3, a key subunit of the A-type potassium current (I_TO), is essential for the proper electrical function of cardiac and neuronal cells by contributing to the regulation of action potential duration and excitability. RBFOX2: RNA-binding protein fox-1 homolog 2, a key regulator of alternative splicing, plays a crucial role in heart development and function, particularly in the context of diabetic cardiomyopathy and cardiovascular disease. S100A11: S100 calcium-binding protein A11, a key regulator in calcium-dependent signaling pathways, plays a crucial role in modulating actin dynamics and myosin ATPase activity, essential for cellular function and heart physiology. ANXA2: Annexin A2, a calcium-binding protein involved in various cellular processes, plays a crucial role in regulating autophagy, inflammation, and angiogenesis, particularly in response to cardiac injury and stress. JunB: Jun B proto-oncogene, a critical transcription factor and member of the AP-1 complex, plays a vital role in regulating gene expression in response to cellular stress, inflammation, and differentiation, significantly impacting cardiovascular function and development.

Figure 4

RNA-binding proteins influence cardiovascular diseases by regulating RNA modification. (a) Hypermethylation due to downregulation of m⁶A eraser protein FTO post-myocardial infarction. (b) FTO expression and hypoxia-induced downregulation limited to cardiac myocytes. (c) FTO demethylation targets identified in mRNA transcripts related to hypertrophy, contractility, filament sliding, and sarcomere organization. (d) The rs9939609 polymorphism in the FTO gene is associated with an increased risk of coronary heart disease. (e) METTL3 overexpression in cardiomyocytes enhances MAP3K6, MAP4K5, and MAPK14 levels and increases cell size. (f) Cardiomyocyte-specific METTL3 knockout induces morphological and functional changes; knockdown accelerates heart regeneration and increases proliferation. FTO: Fat mass and obesity-associated protein, an essential regulator of RNA methylation, plays a crucial role in modulating cardiac function and protecting against myocardial ischemia-reperfusion injury by influencing gene expression stability and cellular responses such as apoptosis and inflammation. METTL3: Methyltransferase-like 3, an essential RNA methyltransferase, plays a crucial role in regulating cardiac function and protecting against myocardial ischemia-reperfusion injury by modulating mitochondrial dynamics and cellular responses, including inflammation and apoptosis. MAP3K6: Mitogen-activated protein kinase kinase kinase 6, a crucial upstream kinase in the MAPK signaling pathway, plays a pivotal role in regulating cellular responses to stress, such as apoptosis and inflammation, by activating downstream kinases including p38 and JNK, which are essential for the progression of myocardial injury and other stress-related cellular processes. MAP4K5: Mitogen-activated protein kinase kinase kinase kinase 5, an upstream regulator in the MAPK signaling cascade, functions by activating MAP3K6 and other MAP3Ks, thereby influencing the activation of key signaling molecules such as p38 and JNK, and contributing to cellular differentiation, stress response, and apoptosis, particularly in the context of cardiac health. MAPK14: Mitogen-activated protein kinase 14, also known as p38α, is a terminal kinase in the MAPK signaling pathway, directly involved in mediating cellular responses to stress, including inflammation, apoptosis, and differentiation, and plays a critical role in the pathogenesis of myocardial ischemia and other cardiovascular diseases.

Figure 5

RNA-binding proteins affect cardiovascular diseases through RNA editing. After transcription, splicing, and 3′ end processing, RBPs guide mRNA from the nucleus to the cytoplasm through a three-step process involving cargo-carrier formation, nuclear pore passage, and cytoplasmic mRNA release with carrier recycling.

Figure 6

The role of RNA-binding proteins in heart muscle injury. ELAV-like protein 1 enhances ferroptosis in myocardial infarction by regulating autophagy, leading to heart muscle damage. In diabetic hearts, the downregulation of RBP QKI-5 increases vulnerability to ischemia by activating FOXO1. Conversely, reintroduction of QKI-5 inhibits ischemia by reducing apoptosis and mitigating stress responses. ELAVL1: ELAV-like protein 1, a protein that plays a critical role in the progression of inflammation and heart failure, is particularly important under hyperglycemic conditions. It regulates cardiac cell death by modulating the expression of caspase-1 and IL-1 beta in cardiomyocytes, and its expression is influenced by miR-9. QKI-5: Quaking isoform 5, one of the three major alternatively spliced isoforms of the quaking (QKI) RNA-binding protein, plays a specific role in regulating RNA processes crucial for cellular functions. It is noted for its broad biological significance in cardiovascular development and neurological disorders. FOXO1: Forkhead box transcription factor O1, a protein that responds to cellular stimulation and maintains tissue homeostasis by modulating downstream targets including apoptosis- and autophagy-associated genes, anti-oxidative stress enzymes, cell cycle arrest genes, and metabolic and immune regulators. It is involved in multiple signaling pathways through post-transcriptional modifications such as phosphorylation, ubiquitination, acetylation, and others, which activate or inhibit its function.

Figure 7

The relationship between myocardial infarction and RNA-binding proteins. In MI, LIN28A activates Sirt1 to induce autophagy and inhibit apoptosis in cardiomyocytes, promoting repair and regeneration. RbFox1 and RbFox2 play a critical role in regulating the alternative splicing of the Ca_v1.2 calcium channel, which influences calcium influx in smooth muscle cells, leading to abnormal vascular contraction and contributing to myocardial infarction. After MI, reduced expression of SRSF3 results in abnormal mTOR mRNA decapping and alternative splicing, affecting the phosphorylation of 4E-BP1, which can be fatal in severe cases. LIN28A: lin-28 homolog A, a master regulator of cellular metabolism, plays a crucial role in heart development. SIRT1: sirtuin 1, a member of the NAD+-dependent deacetylases family, plays a crucial role in regulating thrombosis, modulating key pathways including endothelial activation, platelet aggregation, and coagulation. RbFox1 and RbFox2: RNA-binding protein fox-1 homolog 1 and 2 regulates the alternative splicing of the Cav1.2 calcium channel, influencing calcium influx and vascular contraction in smooth muscle cells. SRSF3: serine/arginine-rich splicing factor 3, an RNA-binding protein crucial for cardiomyocyte proliferation and cardiac homeostasis, plays a significant role in mRNA splicing and the prevention of systolic heart failure. mTOR: mammalian target of rapamycin, a key regulator of cell growth, proliferation, and survival, plays a pivotal role in cardiac function and homeostasis.

Figure 8

RBP expression variations: implications for cardiac disease. LIN28A enhances stem cell proliferation and heart failure recovery by upregulating lncRNA H19 and interacting with let-7 miRNA, while heart failure is linked to YTHDF2 overexpression and malfunctioning SCN5a splice variants influenced by RBM25 and LUC7L3 in response to cardiac stress. RBPs in cardiac health and disease: a molecular interplay. Mutations in TDP-43 and CUGBP1 overexpression cause cardiovascular issues and heart failure, with reactivation of fetal RBPs and abnormal RBFOX2 and QKI expression impacting heart function, highlighting their roles in cardiac disease, including diabetes and drug-induced conditions. RBFOX2: RNA-binding protein fox-1 homolog 2, a key regulator of alternative splicing, plays a crucial role in heart development and function, particularly in the context of diabetic cardiomyopathy and cardiovascular disease. YTHDF2: YT521-B homology domain family 2, an RNA m⁶A reader protein, regulates cardiomyocyte size and apoptosis, and plays a crucial role in cardiac function, metabolism, and the physiological response to exercise. SCN5a: sodium voltage-gated channel alpha subunit 5, a critical component of cardiac electrical impulse initiation and conduction, plays a crucial role in heart rhythm regulation, particularly in the context of arrhythmias such as long QT syndrome, Brugada syndrome, and sudden infant death syndrome. LUC7L3: LUC7-like 3 pre-mRNA splicing factor, a splicing regulatory protein, indirectly modulates cardiac function by influencing the alternative splicing of key genes such as SCN5A, playing a crucial role in heart rhythm regulation and the pathogenesis of heart failure. RBM25: RNA-binding motif protein 25, a splicing regulatory protein, influences cardiac function by modulating the alternative splicing of critical genes like SCN5a, playing a significant role in the regulation of heart rhythm and contributing to the pathogenesis of heart failure. TDP-43: TAR DNA-binding protein 43, a protein implicated in the formation of neuronal and glial inclusions, plays a crucial role in the pathology of amyotrophic lateral sclerosis (ALS) and is associated with aggregates in skeletal and cardiac muscles in various neuromuscular diseases. CUGBP1: CUG-binding protein 1, a multifunctional RNA-binding protein, is crucial for the regulation of mRNA splicing, stability, and translation in various tissues, including the myocardium, playing an essential role in myofibril organization, cell proliferation, and morphogenesis during cardiac development.