Nicorandil protects against cardiac I/R injury via Mt2-mediated mitochondrial homeostasis

Myocardial ischemia/reperfusion (I/R) injury frequently induces adverse cardiac remodeling and dysfunction. Nicorandil (NIC) exhibits cardioprotective effects, whereas its precise mechanisms against I/R injury remain incompletely elucidated. We employed I/R model using C57BL/6 J mice pretreated with NIC. Echocardiography, TTC-Evans blue staining, electron microscopy, qPCR, immunoblotting, and pathological staining were used to investigate the effect of NIC. We found that NIC ameliorated I/R-induced cardiac dysfunction and myocardial infarction in a dose-dependent manner, while also mitigating the pathological features associated with inflammation, oxidative stress, fibrosis, and mitochondrial dysfunction. Mechanistically, these protective effects were attributed to the upregulation of Mt2. Cardiac-specific Mt2 knockdown abolished the beneficial effects of NIC on mitochondrial dynamics, bioenergetics and ATP production. Furthermore, NIC cardiac protection was associated with Mt2-dependent activation of the LKB1-AMPK signaling axis, suggesting a mechanism by which Mt2 contributes to improved myocardial energy metabolism. These findings establish Mt2 as a pivotal target for NIC mediated cardioprotective effects and propose a novel therapeutic strategy to alleviate I/R injury. • Nicorandil upregulates Mt2 to alleviate myocardial I/R injury. • Cardiac-specific Mt2 knockdown abolished the beneficial effects of Nicorandil. • Mt2 may be a novel therapeutic strategy to alleviate I/R injury.