The Cardioprotective Effects Of Carvedilol On Ischemia And Reperfusion Injury By AMPK Signaling Pathway

Objectives:Carvedilol,a third generation beta blocker,is in clinical use for heart failure patients.However,besides adrenergic receptor blockade,the pharmacological effects of carvedilol on cardiomyocytes remain unknown.AMP-activated protein kinase(AMPK)is an emerging target recognized for heart failure treatment.Methods:Mice ischemia-reperfusion model was bild to study the protective effect of carvedilol on myocardium.The effect of carvedilol on cardiac metabolism during ischemia-reperfusion injury was measured by isolated heart.The contractile function and intracellular Ca2+properties weremeasured in isolated cardiomyocyte contractile functions in response to ischemic stress,and the mechanism of carvedilol affecting the contractility of cardiomyocytes was studied by observation of intracellular Ca2+signal level.Results:Mice treated with Carvedilol followed by left coronary artery occlusion and reperfusion showed significant size reduction in infarcted myocardium and improved cardiac functions.In mouse hearts perfused ex vivowith Carvedilol,the function ofpost-ischemia left ventricle was improved commensurately with an increase in cardiac AMPK activation and an augmentation in myocardial glucose uptake and glucoseoxidation.By contrast,Carvedilol treatment had little effectin cells or tissues genetically deficient in AMPK activity,verifying the specificity of Carvedilol for cardioprotective effects through AMPK signaling.Treatment of cardiomyocytes with carvedilol augmented AMPK phosphorylation,increased by 40%the surface localization of glucose transporter,and enhanced by 30%glucose uptake(p<0.05 versus control).The protective effect of Carvedilol wasalso supported in isolated cardiomyocyte.Carvedilol treatment ameliorated hypoxia andre-oxygenation(H/R)-induced impairment in maximal velocity of shortening(+dL/dt)and relengthening(-dL/dt),and the impaired peak height and peak shortening(PS)amplitude caused by H/R.In addition,the results of Western Blot confirmed that carvedilol activated AMPK under hypoxic conditions.Conclusions:The data supports the pharmacological utility of Carvedilol in enhancing AMPK activation and reducing cardiac ischemic injury.