Abstract

Myocardial ischemia/reperfusion (I/R) injury frequently occurs in acute coronary artery disease after timely reperfusion to rescue the ischemic heart. AMP-activated protein kinase (AMPK) is a key sensor that regulates metabolic metabolism and mitochondrial function and protects against myocardial I/R injury. Thus, pharmacologically activating AMPK modulation of AMPK has been suggested as a potential approach for attenuating myocardial I/R injury. MK-3903 is a potent and selective activator of AMPK, but its importance and mechanism of action in modulating this disease remain unclear. I/R was modeled in wild-type mice pretreated with MK-3903 (30 mg/kg). In addition, hypoxia/reoxygenation (H/R) was modeled using neonatal rat cardiomyocytes (NRCMs), and these cells were treated with MK-3903 and SR-18292 (a PGC-1α inhibitor). Our results revealed that in I/R model mice, the administration of MK-3903 dramatically alleviated myocardial dysfunction; reduced the infarct size, myocyte apoptosis, oxidative stress and inflammation; along with increased AMPK-PGC-1α signaling, improved imitochondrial biogenesis and the balance of mitochondrial dynamics. Conversely, the treatment of NRCMs with SR-18292 markedly diminished the cardioprotective effects of MK-3903 following H/R in vitro . In conclusion, these data demonstrate that MK-3903 may attenuate myocardial I/R injury and mitochondrial dysfunction possibly by activating AMPK-PGC-1α signaling and highlight its potential as a candidate for further investigation in ischemic heart injury.