N6-methyladenine demethylase ALKBH5 alleviates cardiomyocytes apoptosis via modulating m6A/SIRT1 manner

Abstract Recent studies have shown that the potential regulatory role of N6-methyladenine (m6A) modification may affect the occurrence and development of various cardiovascular diseases. However, the regulatory mechanism of m6A modification on myocardial ischemia reperfusion injury (MIRI) is rarely reported. A mice model of myocardial I/R was established by ligation and perfusion of the left anterior descending coronary artery, and a cellular model of H/R was conducted in cardiomyocytes (CMs). We found that the protein expression of ALKBH5 in myocardial tissues and cells were decreased, accompanied by increased m6A modification levels. Overexpression of ALKBH5 significantly inhibited H/R induced oxidative stress and apoptosis in CMs. Mechanistically, deacetylases Sirtuin-1(SIRT1), a master regulator of oxidative stress, apoptosis and endothelial function genes, at enriched m6A motif in the 3’-UTR, which promotes the stability of SIRT1 mRNA. Furthermore, overexpression or knockdown of SIRT1 confirmed the protective effect of SIRT1 on H/R induced CMs apoptosis. Together, our study reveals a critical mechanism between ALKBH5-medicated m6A and CM apoptosis, supplying an important regulating effect of m6A methylation in ischemic heart disease.