Retraction

Abstract

Methyltransferase-like 3 (METTL3) mediated N⁶-methyladenosine (m6A) promotes microRNAs (miRNAs) maturation by processing the primary miRNAs (pri-miRNAs), and METTL3 involves in regulating the development of various diseases, including myocardial ischemia-reperfusion (I/R) injury. However, up until now, the association between METTL3 regulated miRNAs and I/R injury is not fully investigated, which makes investigations on this academic issue necessary. In this study, we showed that METTL3 was downregulated in mice I/R myocardial tissues and hypoxic/re-oxygenated (H/R) cardiomyocytes, and upregulation of METTL3 attenuated I/R and H/R-induced cell apoptosis. In addition, we screened out that two miRNAs, including miR-25-3p and miR-873-5p, were positively regulated by METTL3 in cardiomyocytes in a DGCR8-dependent manner. In addition, both miR-25-3p and miR-873-5p were significantly downregulated by I/R and H/R treatments in mice tissues and cardiomyocytes, and overexpression of the above two miRNAs were effective to improve cell viability in cardiomyocytes under H/R stress. Next, we evidenced that METTL3 suppressed H/R-induced cell death via upregulating miR-25-3p and miR-873-5p. Finally, the potential downstream mechanisms were investigated, and we expectedly found that METTL3 activated the PI3K/Akt pathway in H/R-treated cardiomyocytes through modulating miR-25-3p and miR-873-5p, and the PI3K/Akt pathway inhibitor (LY294002) abrogated the protective effects of METTL3 overexpression in cardiomyocytes with H/R treatment. Collectively, we concluded that METTL3 upregulated miR-25-3p and miR-873-5p to activate the PI3K/Akt pathway, resulting in the suppression of I/R injury.