Mitochondrial Dysfunction and Apoptosis Are Attenuated on κ-Opioid Receptor Activation Through AMPK/GSK-3β Pathway After Myocardial Ischemia and Reperfusion

Previous studies have shown that kappa-opioid receptor activation possesses cardioprotection against myocardial ischemia and reperfusion (MFR) injury. The current study was designed to investigate whether mitochondrial dysfunction after MFR. is regulated by the kappa-opioid receptor and to further explore the underlying mechanisms involved. MFR. rat model was established in vivo, and a hypoxia and reoxygenation cardiomyocytes model was used in vitro. Mitochondrial morphology and function as well as myocardial apoptosis were determined. Our data indicated that treatment with U50,488H (a selective kappa-opioid receptor agonist) not only reduced apoptosis but also significantly improved mitochondrial morphology and function. These effects were blocked by norbinaltotphimine (nor-BNI, a selective kappa-opioid receptor antagonist), Compound C (an AMPK inhibitor), and AR-A014418 (a GSK3 beta inhibitor). Moreover, in cardiomyocytes, treatment with U50,488H significantly increased the expression in phosphorylation of AMPK and the phosphorylation of GSK3 beta. Treatment of cardiomyocytes with AMPK alpha siRNA decreased the phosphorylation of AMPK and GSK3 beta. Moreover, AMPK activation resulted in the phosphorylation of GSK3 beta. Our findings suggested that U50,488H exerted cardioprotective effects by improving mitochondrial morphology and function against MI/R injury through activation of the kappa-opioid receptor-mediated AMPK/GSK3 beta pathway.