Inhibition of mitochondrial permeability transition pore restores the cardioprotection by postconditioning in diabetic hearts

Abstract

BackgroundCardiovascular risk factors, including diabetes mellitus may attenuate the cardioprotection by postconditioning. This study aimed to investigate the cardioprotective effect of ischemic-postconditioning (IPostC) against ischemia/reperfusion injury in normal and chronically type-1 diabetic rats and the effect of mitochondrial permeability transition pore (mPTP) inhibition in this field.MethodsDiabetes was induced by a single intra-peritoneal injection of streptozotocin (50 mg/kg) in Wistar male rats (250-300 g). After 8 weeks, the hearts of control and diabetic animals were isolated and mounted on a constant-pressure Langendorff apparatus. All hearts were subjected to 30 min regional ischemia followed by 45 min reperfusion (by occluding and re-opening of LAD coronary artery, respectively). At the end of ischemia, the hearts received IPostC, cyclosporine-A, or both or none of them. Myocardial creatine-kinase (CK) release as an index of tissue injury was measured spectrophotometery in coronary effluent in reperfusion phase. Infarct size was identified by triphenyltetrazolium chloride staining. Heart rate, left ventricular end-diastolic pressure (LVEDP), LV systolic pressure (LVSP), rate-pressure product (RPP) and coronary flow were recorded throughout the experiment.ResultsIPostC, applied at the onset of reperfusion, failed to improve myocardial LVEDP and RPP, or reduce tissue damage indicated by infarct size and CK release in diabetic hearts, while it significantly recovered these parameters toward the pre-ischemic values in control hearts (P < 0.05). In contrast, with simultaneous inhibition of mPTP using cyclosporine-A, the cardioprotective effects of IPostC on myocardial hemodynamics, infarct size and CK release were significantly restored in diabetic hearts (P < 0.05).ConclusionsThe loss of cardioprotection by IPostC in diabetic state can be overcome by increasing the potency of protective IPostC through its co-application with mPTP inhibition.

Ischemic postconditioning provides cardioprotective and antiapoptotic effects against ischemia–reperfusion injury through iNOS inhibition in hyperthyroid rats

“…Higher values of LDH and CK-MB levels in the coronary effluent of hyperthyroid rats, compared to controls indicate higher susceptibility of the heart of hyperthyroid rats to IR (Venditti et al, 2002). Similar to the effects observed on iNOS and eNOS expression in our study, IPost reduced LDH and CK-MB levels in hyperthyroid rats only in the presence of decreased NO production by iNOS, findings similar to those observed in diabetic rats in which IPost alone could not reduce CK-MB; however IPost in the presence of cyclosporine-A (CsA), an inhibitor of mPTP (mitochondrial permeability transition pore), provided cardioprotection (Najafi et al, 2014); somewhat similar to their findings we also founds that applying IPost, in the presence of iNOS inhibition in control rats, had no significant additive effect on the reduction of CK-MB and LDH level.…”

Effect of ischemic postconditioning on myocardial protection in patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass

“… 21 - 23 The mPTP and mitoK-ATP channels play important roles in the regulation of mitochondrial membrane potential and matrix size and volume, by which they preserve the mitochondrial function and integrity during I/R injuries and thus protect the heart against these circumstances. 9 , 24 - 26 …”

Effects of troxerutin on vascular inflammatory mediators and expression of microRNA-146a/NF-κB signaling pathway in aorta of healthy and diabetic rats

“…The development of diabetes was confirmed by measuring the blood glucose levels, 72 h after injection. The animals with blood glucose levels higher than 300 mg/dl were considered diabetic and those with blood glucose levels lower than this value were excluded from the experiment [14]. After six weeks of STZ injection, troxerutin (150 mg/kg/day) was administered orally for four weeks [15].…”