Introduction: Cardiac fibrosis is a key pathological driver of cardiovascular diseases (CVDs). N6-methyladenosine (m6A) regulates mRNA metabolism. While our previous findings established m6A's role in endothelial cell angiogenesis following ischemic injury, its impact on cardiac fibrosis remains unknown. This study explores the role of m 6 A mRNA methylation in fibroblast activation, focusing on METTL3-mediated β-catenin signaling. We hypothesize that ischemia-induced METTL3 activation stabilizes CTNNB1 mRNA, promoting fibrosis, while METTL3 inhibition reduces myofibroblast activation and adverse remodeling. Method: We first reanalyzed available datasets to identify fibrosis-regulating targets in Sham and myocardial infarction (MI) hearts. Methylation patterns were then examined in vivo using myoFB METTL 3 knockout (KO) mice and through pharmacological inhibition of METTL3 with STM 2457 in MI mice. Cardiac function was assessed via echocardiography. In vitro methylation dynamics, fibrotic gene expression, and β-catenin regulation were studied in ischemic cardiac fibroblasts for mechanistic analysis. An Actinomycin D assay was performed to evaluate the role of methylation in β-catenin mRNA stability. Result: The reanalysis of the available dataset revealed an upregulation of β-catenin expression with multiple methylation sites. Myocardial infarction increased global m 6 A methylation in the mouse heart. In contrast, METTL 3 inhibition via STM 2457 significantly improved cardiac function post-MI by reducing β-catenin mRNA methylation, β-catenin expression, and fibrosis. MyoFBMETTL3KO mice exhibited decreased METTL3 expression, enhanced cardiac function (percentage ejection fraction and fractional shortening), and reduced fibrosis. Interestingly, ischemic stress induces mRNA methylation that stabilizes β-catenin mRNA in cardiac fibroblasts. Conclusion: Increased β-Catenin m6A mRNA methylation exacerbated cardiac fibrosis post- MI. Inhibition of mRNA methylation reduced MI-induced cardiac fibrosis, highlighting STM 2457 as a potential therapeutic candidate for treating heart failure.
Dutta et al. (Fri,) studied this question.