m(6)A eraser ALKBH5 mitigates the apoptosis of cardiomyocytes in ischemia reperfusion injury through m(6)A/SIRT1 axis

Recent studies have shown that the potential regulatory role of N(6)-methyladenine (m(6)A) modification may affect the occurrence and development of various cardiovascular diseases. However, the regulatory mechanism of m(6)A modification on myocardial ischemia reperfusion injury (MIRI) is rarely reported. A mouse model of myocardial ischemia reperfusion (I/R) was established by ligation and perfusion of the left anterior descending coronary artery, and a cellular model of hypoxia/reperfusion (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 m(6)A modification level. Overexpression of ALKBH5 significantly inhibited H/R-induced oxidative stress and apoptosis in CMs. Mechanistically, there was an enriched m(6)A motif in the 3′-UTR of SIRT1 genome, and ALKBH5 overexpression promoted the stability of SIRT1 mRNA. Furthermore, results using overexpression or knockdown of SIRT1 confirmed the protective effect of SIRT1 on H/R induced CMs apoptosis. Together, our study reveals a critical role of ALKBH5-medicated m(6)A on CM apoptosis, supplying an important regulating effect of m(6)A methylation in ischemic heart disease.