Dexmedetomidine plays a protective role in sepsis-associated myocardial injury by repressing PRMT5-mediated ferroptosis

Sepsis rapidly contributed to multiorgan failure, most typically damaging the cardiovascular system, and there were no effective treatments. Dexmedetomidine (Dex) has good therapeutic effects on sepsis-induced organ injury. Our work aimed to probe the pharmacological effects of Dex on ferroptosis in sepsis-associated myocardial injury (S-MI) and define underlying mechanism of action. Cardiomyocytes were exposed to lipopolysaccharide (LPS) for mimicking S-MI model in vitro. The septic mice were constructed by cecum ligation and puncture operation. The mRNA and protein expressions were assessed using quantitative real-time polymerase chain reaction or western blot. Cell survival was determined by cell counting kit-8, lactic dehydrogenase release, and flow cytometry assays. 2',7'-Dichlorodihydrofluorescein diacetate staining measured cellular reactive oxygen species level. The secretion levels of inflammatory cytokines, ferroptosis-related indicators were analyzed by enzyme-linked immunosorbent assay. The N6-methyladenosine (m6A) modification level of protein arginine methyltransferase 5 (PRMT5) mRNA was examined by methylated RNA binding protein immunoprecipitation (Me-RIP) assay. The interaction between methyltransferase like 3 (METTL3)/fat mass and obesity-associated protein (FTO) and PRMT5 was analyzed by RNA immunoprecipitation assay. Dex treatment alleviated LPS-induced cardiomyocyte injury and ferroptosis, while these effects of Dex were reversed by Erastin treatment. Mechanically, Dex ameliorated PRMT5 expression in LPS-induced cardiomyocytes by regulating METTL3/FTO catalyzed m6A modification on PRMT5 mRNA. Rescue experiments confirmed that PRMT5 overexpression abolished Dex-mediated inhibitory roles on LPS-induced cardiomyocyte injury and ferroptosis. Moreover, Dex administration alleviated inflammation, ferroptosis, and myocardial injury in septic mice. Taken together, Dex repressed PMRT5 expression in a m6A-dependent manner, thus lightening LPS-triggered ferroptosis to alleviate cardiomyocyte injury.