Irisin attenuates myocardial ischemia/reperfusion‐induced cardiac dysfunction by regulating ER‐mitochondria interaction through a mitochondrial ubiquitin ligase‐dependent mechanism

作者：Linhe Lu, Jipeng Ma, Jiayou Tang, Liu Yang, Qijun Zheng, Shasha Chen, Erhe Gao, Jun Ren, Lifang Yang, Jian Yang · 发表于：Clinical and Translational Medicine · 年份：2020 · DOI：10.1002/ctm2.166 · 被引用次数：84 · 研究领域：Adipose Tissue and Metabolism、Mitochondrial Function and Pathology、Eicosanoids and Hypertension Pharmacology

BACKGROUND: Myocardial ischemia/reperfusion (MI/R) injury imposes devastating cardiovascular sequelae in particular cardiac dysfunction as a result of restored blood flow. However, the mechanism behind MI/R injury remains elusive. Mitochondrial ubiquitin ligase (MITOL/MARCH5) is localized at the mitochondria-ER contact site and may be activated in response to a variety of pathophysiological processes, such as apoptosis, mitochondrial injury, ER stress, hypoxia, and reactive oxygen species (ROS) generation. Irisin as a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) displays cardioprotection in diverse cardiac diseases. METHODS: This study was designed to examine the role of irisin and MITOL in MI/R injury. Male C57BL/6J mice (8-10-week-old) were administered adenovirus MITOL shRNA through intracardiac injection followed by MI/R surgery through ligation and release the slipknot of cardiac left anterior descending coronary artery. RESULTS: Our results showed that irisin improved myocardial function in the face of MI/R injury as evidenced by reduced myocardial infarct size, apoptotic rate, serum lactate dehydrogenase (LDH), ROS generation, and malondialdehyde (MDA) levels as well as lessened ER stress injury. Moreover, our results indicated that protective role of irisin was mediated by upregulation of MITOL. Irisin also protected H9c2 cells against simulated I/R through negating ER stress, apoptosis, ROS and MDA levels, as well as facilitating supero...