Biological function of RNA-binding proteins in myocardial infarction: a potential emerging therapeutic limelight

Abstract

Myocardial infarction (MI) is currently one of the most fatal cardiovascular diseases worldwide. The screening, treatment, and prognosis of MI are top priorities for cardiovascular centers globally due to its characteristic occult onset, high lethality, and poor prognosis. MI is caused by coronary artery occlusion induced by coronary atherosclerotic plaque blockage or other factors, leading to ischemic necrosis and apoptosis of cardiomyocytes. Although significant advancements have been made in the study of cardiomyocytes at the cellular and molecular levels, RNA-binding proteins (RBPs) have not been extensively explored in the context of MI. RBPs, as key regulators coordinating cell differentiation and tissue homeostasis, exhibit specific functions in gene transcription, RNA modification and processing, and post-transcriptional gene expression. By binding to their target RNA, RBPs coordinate various RNA dynamics, including cellular metabolism, subcellular localization, and translation efficiency, thereby controlling the expression of encoded proteins. Classical RBPs, including HuR, hnRNPs, and RBM family molecules, have been identified as critical regulators in myocardial hypoxia, oxidative stress, pro-inflammatory responses, and fibrotic repair. These RBPs exert their effects by modulating key pathophysiological pathways in MI, thereby influencing specific cardiac outcomes. Additionally, specific RBPs, such as QKI and fused in sarcoma (FUS), are implicated in the apoptotic pathways activated during MI. This apoptotic pathway represents a significant molecular phenotype in MI, offering novel perspectives and insights for mitigating cardiomyocyte apoptosis and attenuating the progression of MI. Therefore, this review systematically summarizes the role of RBPs in the main pathophysiological stages of MI and explores their potential therapeutic prospects.

Keywords: Alternative splicing; Myocardial infarction; Post-transcriptional modification; RNA-binding proteins.

Fig. 1

RBPs participate in the whole process of mRNA metabolic cycle. RBPs play a critical role in coordinating various mRNA processes, including polyadenylation, alternative splicing, editing, organelle localization, translation, and decay. Specifically, it encompasses: pre-regulatory mRNA processing; 5’ capping; 3’ polyadenylation; alternative splicing to retain novel codons or introns; facilitation of mRNA nucleocytoplasmic transport; regulation of mRNA subcellular localization, and targeted mRNA degradation

Fig. 2

Dynamic characteristics and pathophysiological processes of subcomponents from healthy heart to post-myocardial infarction heart. The main components of myocardial tissue include cardiomyocytes, cardiac immune cells, cardiac fibroblasts, and endothelial cells. When the heart is subjected to hypoxic stress, these diverse cell types exhibit distinct outcomes or undergo a series of adaptive changes in response to the stimulus, ultimately stabilizing. Among these cell types, cardiomyocytes undergo ischemic hypoxia-induced apoptosis and necrosis; macrophages mediate inflammatory damage and polarization; and cardiac fibroblasts and endothelial cells undergo dynamic changes, including migration, proliferation, and differentiation, which significantly influence the recovery of cardiac morphology and function

Fig. 3

A cluster of RBPs in cardiomyocytes regulates target mRNA. a: Under hypoxic conditions, a cluster of RBPs enhances glucose utilization by improving the transcription and translation efficiency of glucose transporters and glycolytic-related proteins. b: As a common and representative molecule within this cluster of RBPs, HuR regulates target mRNA through various mechanisms under hypoxic conditions. HuR can be regulated through four primary mechanisms: (1) binding to the AU-rich elements (ARE) on target mRNA and inducing nuclear-cytoplasmic shuttling; (2) binding to ARE elements on target mRNA to modulate its stability; (3) co-regulating target mRNA with non-coding RNAs; and (4) regulating the methylation modification of target mRNA

Fig. 4

RBPs participate in methylation modification and regulate oxidative stress in cardiomyocytes. Methylation is commonly mediated by the writer complex METTL3/METTL14 and the reader protein YTHDF2, which promote methylation modifications and regulate the stability of target mRNAs (e.g., SLC7A11 and BNIP3). This process modulates mitochondrial stress and ROS production

Fig. 5

RBPs cooperated with non-coding RNA to regulate apoptosis of cardiomyocytes. In the nucleus, pre-miRNA is processed to generate three types of circ-RNAs. Among these, exon-intron circRNA (EIciRNA) and circular intronic RNA (CiRNA) function exclusively in transcriptional regulation within the nucleus. As the predominant form of circRNA, exonic circRNA (ecRNA) undergoes processing and is subsequently transported to the cytoplasm where it forms mature circular RNA. Similar to miRNA, ecRNA can function as a protein sponge, binding to RBPs such as EGR1, E2F1, FUS, and QKI. This interaction modulates RBP activity and consequently influences the apoptotic processes in MI

Fig. 6

RBPs primarily participate in three key processes: (1) the transformation of fibroblasts into myofibroblasts, (2) endothelial-to-mesenchymal transition, and (3) the regulation of collagen fiber formation. Under TGF-β stimulation, the RNA-binding proteins MBNL1, PUM2, and QKI coordinately regulate fibroblast-to-myofibroblast transdifferentiation through enhanced transcriptional and translational control, thereby promoting cardiac fibrosis progression. In addition, both Csede1 and HnRNP restrain each other and maintain balance, which is of vital significance for maintaining the dynamic balance of endothelial mesenchymal. PTBP1 and hnRNP A1/E1 have also been found to promote the stability of collagen target mRNA and aggravate cardiac fibrosis

Fig. 7

Representative RBPs play a pivotal role in the five major pathophysiological stages of MI: hypoxia, oxidative stress, inflammation, apoptosis, and fibrosis