METTL3 achieves lipopolysaccharide-induced myocardial injury via m6A-dependent stabilization of Myh3 mRNA.

Septic cardiomyopathy (SCM) was an important pathological component of severe sepsis and septic shock. N6-methyladenosine (m6A) modification was a common RNA modification in both mRNA and non-coding RNAs and was proved to be involved in sepsis and immune disorders. Therefore, the purpose of this study was to investigate the role and mechanism of METTL3 in lipopolysaccharide-induced myocardial injury. We firstly analyzed the expression changes of various m6A-related regulators in human samples in the GSE79962 data and the Receiver Operating Characteristic curve of significantly changed m6A enzymes, showing that METTL3 had a high diagnostic ability in patients with SCM. Western blotting confirmed the high expression of METTL3 in LPS-treated H9C2 cells, which was consistent with the above results in human samples. In vitro and in vivo, the deficiency of METTL3 could improve the cardiac function, cardiac tissue damage, myocardial cell apoptosis and reactive oxygen species levels in LPS-treated H9C2 cells and LPS-induced sepsis rats, respectively. In addition, we obtained 213 differential genes through transcriptome RNA-seq analysis, and conducted GO enrichment analysis and KEGG pathway analysis through DAVID. We also found that the half-life of Myh3 mRNA was significantly reduced after METTL3 deletion and that Myh3 carried several potential m6A modification sites. In conclusion, we found that downregulation of METTL3 reversed LPS-induced myocardial cell and tissue damage and reduced cardiac function, mainly by increasing Myh3 stability. Our study revealed a key role of METTL3-mediated m6A methylation in septic cardiomyopathy, which may offer a potential mechanism for the therapy of septic cardiomyopathy.