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

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.

An overview of the effects and mechanisms of m6 A methylation on innate immune cells in sepsis

“…The pathophysiological mechanism of sepsis-induced myocardial injury is complex, involving both pathogens and the host immune system. It has also been demonstrated that m 6 A methylation plays a significant regulatory role in sepsis-induced myocardial injury ( 24 ). Shen et al.…”

N6-methyladenosine (m6A) reader IGF2BP1 facilitates clear-cell renal cell carcinoma aerobic glycolysis

“…For example, in gastric cancer, m 6 A reader IGF2BP1 upregulated in gastric cancer tissue and acted as a predictor of poor prognosis for gastric cancer patients and IGF2BP1 directly interacts with c-MYC mRNA via m 6 A-dependent manner to stabilize its stability ( Luo & Lin, 2022 ). In lipopolysaccharide-induced cardiomyocytes, m 6 A reader IGF2BP1 recognizes the m 6 A modified sites on HDAC4 mRNA and enhances its mRNA stability ( Shen et al, 2022 ). Thus, the critical role of IGF2BP1 might promote this tumor progression.…”

Inhibition of IGF2BP1 attenuates renal injury and inflammation by alleviating m6A modifications and E2F1/MIF pathway

“…Apart from the roles in neoplastic diseases, IGF2BP1 is also involved in several nonneoplastic conditions. For example, the role of the METTL3/IGF2BP1/HDAC4 axis was illustrated in sepsis-associated myocardial injury, providing a novel therapeutic strategy 73 . In this study, we found high IGF2BP1 expression in septic AKI and that the level of IGF2BP1 was positively correlated with pyroptosis in renal tubular cells.…”