N6-methyladenosine (m6A) RNA modification in the pathophysiology of heart failure: a narrative review

Abstract

Background and Objective: Heart failure is the end-stage of various cardiovascular diseases.Recent progress in molecular biology has facilitated the understanding of the mechanisms of heart failure development at the molecular level. N6-adenosine methylation (m6A) is a post-transcriptional modification of RNA. Recent research work reported that m6A regulates gene expression and subsequently affects the activation of cell signaling pathways related to heart failure. Moreover, m6A regulators like methyltransferase-like 3 (METTL3) were reported to participate in myocardium hypertrophy. However, the current research work related to the role of m6A participating in the occurrence of heart failure is rare in some aspects like immune cell infiltration and diabetic heart diseases. Thus, it is reasonable to review the current achievements and provide further study orientation. Methods:We searched related literature using the keywords: m6A AND heart failure in PubMed, Web of Science and Medline. The language was confined to English. The published year of searched literature ranged from 2012 to 2022. The searched results were put into Endnote software for management. Two authors investigated the searching terms and reviewed the full text of selected terms.Key Content and Findings: m6A and its regulators are involved in the metabolism of various types of RNAs. m6A modification can regulate various types of cell signaling pathways related to the heart failure via interaction with m6A regulators. m6A and its regulators broadly participate in the myocardium fibrosis, myocardium hypertrophy, myocardial cell apoptosis, and ischemic reperfusion injury. Specifically, m6A participates in the cell apoptosis via regulation of autophagy flux. However, the current research work does not have enough evidence to prove that m6A regulator played its specific effect on the target transcript via regulating the m6A level.Conclusions: m6A and its regulators participates in the progression of heart failure via modifying the RNA level. Future investigation of m6A should focus on the interaction between the m6A regulators and targeted transcript. Besides, the regulation role of m6A in immune cell infiltration and diabetic heart diseases should also be focused.

METTL3 boosts mitochondrial fission and induces cardiac fibrosis after ischemia/reperfusion injury

“…Furthermore, METTL3 has been implicated in cardiac hypertrophy [14], where its m6A RNA methylation mechanism influences the expression of key genes associated with myocardial remodeling, fibrosis, and contractile function [15][16][17]. Dysregulation of METTL3-mediated RNA methylation has also been observed in heart failure models [16,18,19], impacting the expression of genes involved in cardiac function, calcium handling, and energy metabolism. Additionally, METTL3 has been found to modulate the function of vascular smooth muscle cells (VSMCs) by regulating the expression of genes involved in vascular remodeling, contractility, and inflammation [20,21].…”

Long non‐coding RNA linc00659 promotes tumour progression by regulating FZD6/Wnt/β‐catenin signalling pathway in colorectal cancer via m6A reader IGF2BP1

“…11 The process of RNA m6A methylation is dynamic and reversible, and involves three types of proteins: methyltransferases, recognition proteins and demethyltransferases. 12 The significance of RNA m6A modification lies in the role of m6A recognition proteins, also known as "readers," which include proteins with YT521-B homologous structure domains (YTHDFs), such as YTHDF1, YTHDF2, YTHDF3, YTHDC1 and YTHDC2. 13 Other m6A readers include heterogeneous nuclear ribonucleoprotein A2B1 and hnRNPC, which control mRNA fate by regulating mRNA stability, translation, splicing, structure, decay and subcellular localization.…”

“…N6‐methyladenosine (m6A) is the most prevalent modification found in eukaryotic RNA 11 . The process of RNA m6A methylation is dynamic and reversible, and involves three types of proteins: methyltransferases, recognition proteins and demethyltransferases 12 . The significance of RNA m6A modification lies in the role of m6A recognition proteins, also known as “readers,” which include proteins with YT521‐B homologous structure domains (YTHDFs), such as YTHDF1, YTHDF2, YTHDF3, YTHDC1 and YTHDC2 13 .…”