GDF15 Improves Lipopolysaccharide-Induced Myocardial Dysfunction By Inhibiting Cardiomyocyte Ferroptosis Via The SOCS1/GPX4 Signaling Pathway Regulation

Abstract

Septic cardiomyopathy is a cardiac disease with an extremely high mortality rate. Cardiomyocyte ferroptosis is an important pathological process in septic cardiomyopathy, which is attributed to reactive oxygen species (ROS) production and lipid peroxidation. Growth differentiation factor 15 (GDF15) has significant antioxidant effects and exerts therapeutic effects in cardiovascular diseases. However, the function and mechanism of GDF15 in septic cardiomyopathy remain unclear. A sepsis model was established by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg) to C57BL/6 male mice. Subsequently, cardiac function was assessed, indicators of myocardial ROS, lipid peroxidation and ferroptosis were also detected. We found that myocardial systolic function was severely impaired in parallel with ROS accumulation, enhanced lipid peroxidation, and increased cardiomyocyte ferroptosis in septic mice, after injecting GDF15, these adverse changes were markedly reversed. Whereas GDF15 antibody (Ab-GDF15) treatment, which can neutralize GDF15 in the circulation, made adverse cardiac changes worse. In terms of the mechanism, RNA sequencing showed that suppressor of cytokine signaling 1 (SOCS1) is a key regulatory molecule downstream of GDF15. Additionally, GDF15 significantly enhanced the expression of ferroptosis markers glutathione peroxidase 4 (GPX4) by inhibiting SOCS1 expression. Overexpression of SOCS1 reversed the beneficial effects of GDF15 on cardiac function, and promoted cardiomyocyte ferroptosis. Above findings demonstrate that GDF15 improves cardiac function and reduces cardiomyocyte ferroptosis by regulating the SOCS1/GPX4 signaling pathway in septic cardiomyopathy. This experiment provides a basis for further evaluation of GDF15 as a therapeutic agent for septic cardiomyopathy.