Blocking the mitochondrial permeability transition pore with cyclosporine-A can restore cardioprotection of ischemic postconditioning in hypercholesterolemic rat heart

OBJECTIVE: Ischemic postcondi - tioning (IPO) reduces lethal reperfusion injury under normal conditions, but its effectiveness is blocked by hypercholesterolemia (HC). This study aims to determine whether blocking the mi - tochondrial permeability transition pore (mPTP) with cyclosporine-A (CsA) can restore cardiopro - tection of IPO in hypercholesterolemic rat heart. MATERIALS AND METHODS: Isolated rat hearts underwent 30 min global ischemia and 120 min reperfusion. Postconditioning protocol was induced by six cycles of 10s ischemia and 10s reperfusion at the onset of the reperfusion. CsA (0.5 µM or 5 µM) was administered 15 minutes be - fore ischemia. Myocardial infarct size was esti - mated by triphenyltetrazolium chloride (TTC) staining. Cardiomyocyte apoptosis was assessed by TUNEL staining and creatine kinase-MB (CK- MB) was analyzed from coronary effluent. RESULTS: In normocholesterolemia (NC) groups, infarct size, cardiomyocyte apoptosis rate and release of CK-MB were significantly reduced after IPO. These reductions were completely abol - ished by HC, as evidenced by a similar infarct size, cardiomyocyte apoptosis rate and release of CK- MB observed between IPO-HC group and control- NC group, but were restored by IPO combinated with CsA treatment. However, CsA treatment alone could not restore cardioprotection in a state of HC. CONCLUSIONS: Ischemic postconditioning, blocked by hypercholesterolemia may due to the excessive opening of the mPTP. Inhibiting of the mPTP with CsA is able to reverse this loss of cardioprotection.