Abstract
Recent studies have identified that N6-methyladenosine (m6A) extensively participates in the myocardial injury pathophysiological process. However, the role of m6A on sepsis-induced myocardial injury is still unclear. Here, we investigated the functions and mechanism of m6A methyltransferase METTL3 for septic myocardial injury. Results illustrated that the m6A modification level and METTL3 up-regulated in the lipopolysaccharide (LPS)-induced cardiomyocytes (H9C2 cells). Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) revealed the m6A profile of the septic myocardial injury cellular model. Functionally, METTL3 knockdown repressed the inflammatory damage of cardiomyocytes induced by LPS. Mechanistically, we found that HDAC4 had remarkable m6A modification sites on its 3'-UTR genome, acting as the downstream target of METTL3. Besides, m6A reader IGF2BP1 recognized the m6A modification sites on HDAC4 mRNA and enhanced its RNA stability. In conclusion, the findings illustrated a role of METTL3/IGF2BP1/m6A/HDAC4 axis on sepsis-induced myocardial injury, which might provide novel therapeutic strategy for septic myocardial injury.