Involvement of Glycogen Synthase Kinase-3β and Oxidation Status in the Loss of Cardioprotection by Postconditioning in Chronic Diabetic Male Rats.

Reza Badalzadeh,Bahman Yousefi,Shima Mohammadi,Safar Farajnia,Mustafa Mohammadi,Moslem Najafi

doi:10.15171/apb.2015.045

Reza Badalzadeh, Bahman Yousefi + Show 4 more

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https://doi.org/10.15171/apb.2015.045

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Abstract

Diabetes mellitus as a main risk-factor of ischemic heart disease may interfere with postconditioning'scardioprotective effects. This study aimed to investigate the involvement of glycogen synthase kinase-3β (GSK-3β) and oxidation status in chronic diabetes-induced loss of cardioprotective effect of ischemic-postconditioning (IPostC) in Wistar rats. After 8 weeks of induction of diabetes by streptozotocin (50mg/kg), hearts of control and diabetic rats were isolated and mounted on a constant-pressure Langendorff system. All hearts were subjected to 30min regional ischemia followed by 60min reperfusion (by occluding and re-opening of left anterior descending coronary artery, respectively). IPostC was applied immediately at the onset of reperfusion. At the end of reperfusion, the infarct size of myocardium was measured via computerized planimetry. Myocardial contents of malondealdehyde and glutathione as indices of oxidative status were assayed spectrophotometrically and the total and phosphorylated forms of myocardial GSK-3β were quantified through western blotting. IPostC reduced the infarct size of control hearts from 41±2.9% to 28±1.9% (P<0.05), whereas it could not induce significant changes in infarct size of diabetic animals (35±1.8% vs. 39±3.1%). IPostC-induced reduction in malondealdehyde and elevation in glutathione contents were significant only in control not in diabetic hearts. The total forms of GSK-3β were similar in all groups; however, the phosphorylation of GSK-3β (at Ser9) by IPostC was greater in control hearts than diabetics (P<0.01). The failure of cardioprotection by IPostC in diabetic hearts may be attributed to the loss of phosphorylation of GSK-3β and thereby increase in oxidative stress in diabetic states.

Highlights

Ischemic heart disease (IHD) is the main cause of mortality in human societies and cardioprotection against ischemia is a matter of life and death in clinics.[1,2] Ischemic postconditioning (IPostC) is one of the cardioprotective strategies introduced in recent years which had significant effect on reduction of infarct size and improvement of cardiac function after ischemia-reperfusion (IR) injury.[3,4,5] In IPostC strategy, short episodes of reperfusion and ischemia are applied to the heart exactly after a long term ischemia.[6]
This study aimed to investigate the involvement of glycogen synthase kinase-3β (GSK-3β) and oxidation status in chronic diabetes-induced loss of cardioprotective effect of ischemic-postconditioning (IPostC) in Wistar rats
The present study aimed to investigate the involvement of GSK-3β as well as glutathione and lipid peroxidation in the failure of IPostC on cardioprotection of diabetic hearts against IR injury

Summary

Introduction

Ischemic heart disease (IHD) is the main cause of mortality in human societies and cardioprotection against ischemia is a matter of life and death in clinics.[1,2] Ischemic postconditioning (IPostC) is one of the cardioprotective strategies introduced in recent years which had significant effect on reduction of infarct size and improvement of cardiac function after ischemia-reperfusion (IR) injury.[3,4,5] In IPostC strategy, short episodes of reperfusion and ischemia are applied to the heart exactly after a long term ischemia.[6]. Considering the progressive increase of diabetes prevalence in different societies and the high rate of mortality among diabetic patients due to myocardial infarction, cardioprotection against IR injuries in diabetic patients is very important.[9,10] IPostC shows its protective effects through different mechanisms, including activation of certain ion channels and receptors, phosphorylation of intracellular protein kinases, opening/closing of mitochondrial pores, and inhibiting cell necrosis and apoptosis.[4,11] Pathologic conditions like diabetes, especially in chronic phases, may interfere with IPostC in cardioprotection, by changing any one of these mechanisms. The present study aimed to investigate the involvement of GSK-3β as well as glutathione and lipid peroxidation in the failure of IPostC on cardioprotection of diabetic hearts against IR injury

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