Mitochondrial Dysfunction and Apoptosis are Attenuated upon κ-Opioid Receptor Activation via AMPK/GSK-3β Pathway Following Myocardial Ischemia and Reperfusion.

Previous studies have shown that κ-opioid receptor activation possesses cardioprotection against myocardial ischemia and reperfusion (MI/R) injury. The current study was designed to investigate whether mitochondrial dysfunction following MI/R is regulated by the κ-opioid receptor and to further explore the underlying mechanisms involved. MI/R rat model was established in vivo, and a hypoxia and reoxygenation cardiomyocytes model was utilized in vitro. Mitochondrial morphology and function, as well as myocardial apoptosis were determined. Our data indicated that treatment with U50,488H (a selective κ-opioid receptor agonist) not only reduced apoptosis but also significantly improved mitochondrial morphology and function. These effects were blocked by nor-binaltorphimine (nor-BNI, a selective κ-opioid receptor antagonist), Compound C (an AMPK inhibitor), and AR-A014418 (a GSK3β inhibitor). Moreover, in cardiomyocytes, treatment with U50,488H significantly increased the expression in phosphorylation of AMPK and the phosphorylation of GSK3β. Treatment of cardiomyocytes with AMPKα siRNA decreased the phosphorylation of AMPK and GSK3β. Moreover, AMPK activation resulted in the phosphorylation of GSK3β. Our findings suggested that U50,488H exerted cardioprotective effects by improving mitochondrial morphology and function against MI/R injury through activation of the κ-opioid receptor-mediated AMPK/GSK3β pathway.