Involvement of GSK-3β in attenuation of the cardioprotective effect of ischemic preconditioning in diabetic rat heart.
Ischemic preconditioning (IPC) produces cardioprotection by phosphorylation of glycogen synthase kinase-3β (GSK-3β) that inhibits the opening of mitochondrial permeability transition pore (MPTP). The activity of glycogen GSK-3β is elevated during diabetes mellitus (DM). This study investigated the role of GSK-3β in attenuation of cardioprotective effect of IPC in diabetic rat. DM was induced by single administration of streptozotocin (STZ, 50 mg/kg, i.p.). Isolated perfused heart was subjected to 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining and lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) was analyzed in coronary effluent. IPC significantly decreased myocardial infarct size and release of LDH and CK-MB from normal rat heart. The cardioprotective effect of IPC was significantly attenuated in diabetic rat. Four episodes of preconditioning by either of GSK-3β inhibitors, lithium chloride (LiCl, 20 mM), indirubin-3 monooxime (1 μM), and SB216763 (3 μM) significantly reduced the LDH and CK-MB release and decreased infarct size in diabetic rat heart. Perfusion of atractyloside, an opener of MPTP, significantly attenuated, the cardioprotective effect of IPC in normal rat heart, and of GSK-3β inhibitor induced preconditioning in the DM rat heart. Our results suggest that preconditioning with GSK-3β inhibitors in diabetic rat heart may provide a more consistent cardioprotection, as compared to IPC. Also, the mechanism of diabetes mellitus-induced attenuation of cardioprotective effect of IPC involves activation of GSK-3β, due to impaired protective upstream signaling pathways and opening of MPTP during reperfusion.
Department of Pharmacology, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab, India.
Harlokesh Narayan
HN
Yadav
Manjeet
M
Singh
P L
PL
Sharma
D000818:Animals; D001278:Atractyloside / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D052279:Creatine Kinase, MB Form / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D019194:Ischemic Preconditioning; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D013311:Streptozocin
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D001278:Atractyloside; D013311:Streptozocin; D007770:L-Lactate Dehydrogenase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D052279:Creatine Kinase, MB Form