Epicardial tissue derived leptin promotes myocardial injury in metabolic syndrome rats through PKC/NADPH oxidase/ROS pathway

Abstract

Abstract Background The epicardial adipose tissue (EAT) of metabolic syndrome (MetS) is abnormally accumulated with dysfunctional secretion of adipokines, closely relating to cardiac dysfunction. The adipokines leptin has been proven to induce cardiac fibroblasts collagen metabolism disorder in hypertensive left ventricular hypertrophy rats. Purpose The study was designed to identify the effects of EAT-derived leptin on the myocardium of MetS rats and explore the potential molecular mechanisms. Methods and results MetS rat model was established in eight-week-old male Wistar rats by 12 week high-fat diet. MetS rats exhibited increased leptin secretion from EAT, cardiac hypertrophy and diastolic dysfunction with preserved systolic function. The myocardium of MetS rats had abnormal structure and mitochondrial morphology, increased oxidative stress injury and inflammatory factors level, especially the subepicardial myocardium, which was correlated with the EAT-derived leptin level, but not the serum leptin (Figure 1). The EAT was separated from each group rats to prepare EAT-Conditioned Medium (EAT-CM). The H9C2 rat cardiomyoblasts were treated with EAT-CM or leptin, plus various signaling pathway inhibitors. EAT derived leptin from MetS rats promoted mitochondrial oxidative stress and dysfunction, induced mitochondrial pathway apoptosis and inhibited cell viability in H9C2 cardiomyoblasts via PKC/NADPH oxidase/ROS pathway. EAT derived leptin from MetS rats stimulated inflammation in H9C2 cardiomyocytes by promoting AP-1 nuclear translocation via PKC/NADPH oxidase/ROS pathway. Leptin promoted the interaction between p-p47phox and gp91phox in H9C2 cardiomyocytes via PKC, activating NADPH oxidase, increasing ROS generation, and inhibiting cell viability. Conclusions EAT derived leptin induces the MetS related myocardial injury though the following two cooperative ways via PKC/NADPH oxidase/ROS pathway: 1. Inducing mitochondrial pathway apoptosis by promoting mitochondrial oxidative stress and dysfunction; 2. Stimulating inflammation by promoting AP-1 nuclear translocation (Figure 2). The results reveal the potential molecular mechanisms of EAT in MetS related myocardial injury, providing novel insights for the further study of MetS related cardiovascular diseases.Figure 1Figure 2