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

Background: Myocardial ischemia/reperfusion (MI/R) injury imposes devas- tating 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 prod- uct of fibronectin type III domain-containing protein 5 (FNDC5) displays cardio- protection 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 aden- ovirus MITOL shRNA through intracardiac injection followed by MI/R surgery through ligation and release the slipknot ofcardiac left anterior descending coro- nary 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 malondialde- hyde (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 superoxide dismutase (SOD) by way of elevated MITOL expression. Conclusions: To this end, our data favored that irisin pretreatment protects against MI/R injury, ER stress, ROS production, and mitochondrial homeostasis through upregulation ofMITOL. These findings depicted the therapeutic poten- tial of irisin and MITOL in the management of MI/R injury in patients with ST- segment elevation.