LAUSR

Abstract: Previous studies have shown that &kgr;-opioid receptor activation possesses cardioprotection against myocardial ischemia and reperfusion (MI/R) injury. The current study was designed to investigate whether mitochondrial dysfunction after MI/R is regulated by the &kgr;-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 used in vitro. Mitochondrial morphology and function as well as myocardial apoptosis were determined. Our data indicated that treatment with U50,488H (a selective &kgr;-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 &kgr;-opioid receptor antagonist), Compound C (an AMPK inhibitor), and AR-A014418 (a GSK3&bgr; inhibitor). Moreover, in cardiomyocytes, treatment with U50,488H significantly increased the expression in phosphorylation of AMPK and the phosphorylation of GSK3&bgr;. Treatment of cardiomyocytes with AMPK&agr; siRNA decreased the phosphorylation of AMPK and GSK3&bgr;. Moreover, AMPK activation resulted in the phosphorylation of GSK3&bgr;. Our findings suggested that U50,488H exerted cardioprotective effects by improving mitochondrial morphology and function against MI/R injury through activation of the &kgr;-opioid receptor–mediated AMPK/GSK3&bgr; pathway.