Melatonin attenuates lipopolysaccharide-induced acute myocardial injury by regulating KLF4 expression

Abstract

Melatonin (MLT) has been reported to effectively reduce myocardial damage induced by lipopolysaccharide (LPS) in mice. MLT exerts its protective effects through multiple mechanisms, including antiferroptosis. This study investigated the relationship between MLT and ferroptosis in patients with sepsis-induced cardiomyopathy (SIC). We demonstrated that pretreatment with MLT improved cardiac contractile function and reduced myocardial injury in mice with sepsis. Furthermore, MLT attenuated the adverse effects of LPS on cardiac contractility in time- and concentration-dependent manners. MLT enhances the antioxidant capacity of tissues and alleviates LPS-induced mitochondrial damage in myocardial tissues. Following intraperitoneal LPS injection in mice, both protein and mRNA levels of KLF4 in myocardial tissue were significantly reduced. MLT pretreatment restored KLF4 protein expression in the myocardium of LPS-injured mice and increased that of antiferroptosis proteins. Notably, KLF4 overexpression stimulated via adeno-associated virus 9 (AAV9) through tail vein injection attenuated LPS-induced cardiac damage in mice. Similarly, in AC16 cells, LPS treatment reduced KLF4 expression, while MLT treatment upregulated it. However, this upregulation was inhibited by an melatonin receptor 1 (MT1) receptor antagonist, suggesting that MLT enhances KLF4 through MT1-dependent signaling. Pretreatment with MLT increased the antioxidant capacity of LPS-stimulated AC16 cells, reduced lipid peroxide levels, and increased the expression of antiferroptosis proteins. Furthermore, the knockdown or overexpression of KLF4 through lentiviral plasmid transfection altered the levels of p62 and YAP, which mirrored the changes in KLF4 expression. Taken together, these findings suggest that MLT protects against SIC through the KLF4-p62-Nrf2 signaling pathway and KLF4/YAP axis.