WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m6A modification of ATF4 mRNA

Abstract

Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m 6 A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m 6 A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP’s effects on myocardial I/R injury were confirmed in vivo . WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m 6 A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

“…m6A is regulated by m6A methyltransferases and demethylases and controls the fate of target mRNA by affecting splicing, translation, and decay. Recently, some researches suggested that m6A modification exhibits importantly in the development of cardiac remodeling and cardiomyocyte contractile function ( Dorn et al, 2019 ; Huang et al, 2019 ; Han et al, 2021 ; Wang et al, 2021 ). For example, ablation of METTL3 weakened MI-caused myocardial fibrosis by impeding the activation of cardiac fibroblasts ( Dorn et al, 2019 ).…”

“…For example, ablation of METTL3 weakened MI-caused myocardial fibrosis by impeding the activation of cardiac fibroblasts ( Dorn et al, 2019 ). WTAP promotes MI via modulating ATF4 ( Wang et al, 2021 ). ALKBH5 mediated the modulation of heart regeneration via demethylating YTHDF1 mRNA ( Han et al, 2021 ).…”

“…Growing evidence indicated that the continuous dynamic modulation of m6A exerts an impact on specific genes’ expression and some diseases’ physiological and pathological processes, including MI, ischemic heart failure (HF), myocardial hypertrophy, and cardiomyogenesis ( Mathiyalagan et al, 2019 ). For instance, WTAP promotes MI via modulating m6A modification of ATF4 mRNA ( Wang et al, 2021 ). Dorn et al (2019) showed that N6 adenosine methylation regulated by METTL3 is crucial for hypertrophy’s pathological process in vivo and in vitro .…”

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

“…Although the study of RNA modifications, epitranscriptomics remains in its infancy, methodological breakthroughs of the last decade have enabled identification of these modifications with such accuracy that their large-scale screening is rational [ 117 , 118 , 119 , 120 , 121 , 143 ]. Encouragingly, research findings suggest both m 6 A and A-to-I to act as contributors or even potential initiators and drivers for several cardiovascular physiological and pathological processes including cardiogenesis, angiogenesis, hypertension, hypertrophy, atherosclerosis, ischemia, ischemia-reperfusion, fibrosis, HF, congenital heart disease, stroke, aneurysms, as well as cardiac repair and regeneration [ 25 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 51 , 52 , 53 , 54 , 55 , 56 ]. Remarkably, the first indication for coronary atherosclerosis to be reflected in the m 6 A content of mRNAs and long non-coding RNAs of peripheral mononuclear cells with suggested involvement in its pathophysiology has just recently been reported [ 151 ].…”

“…Silencing or overexpression of enzymes controlling m 6 A abundance has revealed the role of m 6 A in driving immune reactivity, proliferation, apoptosis, and many intracellular processes including mRNA splicing, translation, and degradation [ 20 , 26 ], as well as miRNA biogenesis [ 27 ]. Moreover, reports from diverse fields of research [ 28 , 29 , 30 , 31 ], and in an array of cardiovascular pathologies [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], provide evidence of m 6 A as a master post-transcriptional regulator.…”