MG53 Protects against Sepsis-Induced Myocardial Dysfunction by Upregulating Peroxisome Proliferator-Activated Receptor-<i>α</i>
Xue Han, Daili Chen, Ning Liufu, Fengtao Ji, Qingshi Zeng, Weifeng Yao, Minghui Cao
Abstract
Background . The heart is one of the most commonly affected organs during sepsis. Mitsugumin-53 (MG53) has attracted attention in research due to its cardioprotective function. However, the role of MG53 in sepsis-induced myocardial dysfunction (SIMD) remains unknown. The purpose of this study was to explore the underlying mechanism of MG53 in SIMD and investigate its potential relationship with peroxisome proliferator-activated receptor- α (PPAR α ). Methods . The cecal ligation and puncture (CLP) model was created to induce SIMD in rats. Protein levels of MG53 and PPAR α , cardiac function, cardiomyocyte injury, myocardial oxidative stress and inflammatory indicators, and cardiomyocyte apoptosis were measured at 18 h after CLP. The effects of MG53 on PPAR α in SIMD were investigated via preconditioning recombinant human MG53 (rhMG53) and PPAR α antagonist GW6471. Results . The expression of MG53 and PPAR α sharply decreased in the myocardium at 18 h after CLP. Compared with the sham group, cardiac function was significantly depressed, which was associated with the destructed myocardium, upregulated oxidative stress indicators and proinflammatory cytokines, and excessive cardiomyocyte apoptosis in the CLP group. Supplementation with rhMG53 enhanced myocardial MG53, increased the survival rate with improved cardiac function, and reduced oxidative stress, inflammation, and myocardial apoptosis, which were associated with PPAR α upregulation. Pretreatment with GW6471 abolished the abovementioned protective effects induced by MG53. Conclusions . Both MG53 and PPAR α were downregulated after sepsis shock. MG53 supplement protects the heart against SIMD by upregulating PPAR α expression. Our results provide a new treatment strategy for SIMD.