METTL3-mediated N6-methyladenosine modification of Trim62 aggravates myocardial ischemia/reperfusion injury by inducing autophagy.
TL;DR
This work indicates that m6A modification plays a critical role in autophagy, likely by downregulating TRIM62 in myocardial I/R, and aggravates myocardial I/R injury by inducing autophagy.
Abstract
Cardiovascular disease (CVD) is a major cause of death worldwide, with ischemic heart disease being an important component of CVD mortality. Data on the expression of TRIM62 and its underlying mechanisms in myocardial ischemia/reperfusion (I/R) injury regulation are scarce. This study aimed to investigate the expression and possible roles of TRIM62 in I/R-induced cardiomyocyte apoptosis and autophagy. I/R injury models were constructed in rats, and hypoxia/re-oxygenation injury was created in H9c2 cardiomyocytes. Myocardial histopathology was confirmed by Hematoxylin & Eosin and TUNEL staining. Cell apoptosis was detected by flow cytometry. Autophagy was measured by immunofluorescence staining and Western blot analysis. N6 methyladenosine (m6A) modification of Trim62 induced by methyltransferase-like 3 (METTL3) was confirmed by RIP-PCR and the Dual-luciferase reporter assay. In vivo, TRIM62 can boost cardiac function and alleviate myocardial I/R injury. The interference of Trim62 expression can inhibit H9c2 cell viability and induce apoptosis by increasing autophagy, and then aggravate hypoxia/re-oxygenation-induced cell injury in vitro. METTL3 promotes m6A modification of Trim62 mRNA and suppresses TRIM62 expression via the m6A reader YTHDF2. Taken together, METTL3-mediated m6A modification of Trim62 aggravates myocardial I/R injury by inducing autophagy. Our work indicates that m6A modification plays a critical role in autophagy, likely by downregulating TRIM62 in myocardial I/R.