N-methyladenosine (mA) methyltransferase METTL3 regulates sepsis-induced myocardial injury through IGF2BP1/HDAC4 dependent manner.

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