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.