N6-methyladenosine (m6A) methyltransferase METTL3 regulates sepsis-induced myocardial injury through IGF2BP1/HDAC4 dependent manner

Recent studies have identified that N-6-methyladenosine (m(6)A) extensively participates in the myocardial injury pathophysiological process. However, the role of m(6)A on sepsis-induced myocardial injury is still unclear. Here, we investigated the functions and mechanism of m(6)A methyltransferase METTL3 for septic myocardial injury. Results illustrated that the m(6)A modification level and METTL3 up-regulated in the lipopolysaccharide (LPS)-induced cardiomyocytes (H9C2 cells). Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) revealed the m(6)A 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 m(6)A modification sites on its 3'-UTR genome, acting as the downstream target of METTL3. Besides, m(6)A reader IGF2BP1 recognized the m(6)A modification sites on HDAC4 mRNA and enhanced its RNA stability. In conclusion, the findings illustrated a role of METTL3/IGF2BP1/m(6)A/HDAC4 axis on sepsis-induced myocardial injury, which might provide novel therapeutic strategy for septic myocardial injury.

Automated summary

Recent studies have shown that m(6)A modification plays a significant role in sepsis-induced myocardial injury. METTL3, a key methyltransferase, regulates the levels of m(6)A modification and affects inflammatory damage in cardiomyocytes. The study also elucidates the mechanism of the METTL3/IGF2BP1/m(6)A/HDAC4 axis in sepsis-induced myocardial injury.