Author:
Gomez Ludovic,Thibault Hélène,Gharib Adbdallah,Dumont Jean-Maurice,Vuagniaux Grégoire,Scalfaro Pietro,Derumeaux Geneviève,Ovize Michel
Abstract
Inhibition of mitochondrial permeability transition pore (mPTP) opening by cyclosporin A or ischemic postconditioning attenuates lethal reperfusion injury. Its impact on major post-myocardial infarction events, including worsening of left ventricular (LV) function and death, remains unknown. We sought to determine whether pharmacological or postconditioning-induced inhibition of mPTP opening might improve functional recovery and survival following myocardial infarction in mice. Anesthetized mice underwent 25 min of ischemia and 24 h ( protocol 1) or 30 days ( protocol 2) of reperfusion. At reperfusion, they received no intervention (control), postconditioning (3 cycles of 1 min ischemia-1 min reperfusion), or intravenous injection of the mPTP inhibitor Debio-025 (10 mg/kg). At 24 h of reperfusion, mitochondria were isolated from the region at risk for assessment of the Ca2+ retention capacity (CRC). Infarct size was measured by triphenyltetrazolium chloride staining. At 30 days of reperfusion, mortality and LV contractile function (echocardiography) were evaluated. Postconditioning and Debio-025 significantly improved Ca2+ retention capacity (132 ± 13 and 153 ± 31 vs. 53 ± 16 nmol Ca2+/mg protein in control) and reduced infarct size to 35 ± 4 and 32 ± 7% of area at risk vs. 61 ± 6% in control ( P < 0.05). At 30 days, ejection fraction averaged 74 ± 6 and 77 ± 6% in postconditioned and Debio-025 groups, respectively, vs. 62 ± 12% in the control group ( P < 0.05). At 30 days, survival was improved from 58% in the control group to 92 and 89% in postconditioned and Debio-025 groups, respectively. Inhibition of mitochondrial permeability transition at reperfusion improves functional recovery and mortality in mice.
Publisher
American Physiological Society
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
170 articles.
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