title: Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice.
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 Ca(2+) 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 Ca(2+) retention capacity (132 +/- 13 and 153 +/- 31 vs. 53 +/- 16 nmol Ca(2+)/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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale E 0226, Université Claude Bernard Lyon I, Lyon, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Gomez
authors.forename: Hélène
authors.initials: H
authors.lastname: Thibault
authors.forename: Adbdallah
authors.initials: A
authors.lastname: Gharib
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Dumont
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vuagniaux
authors.forename: Pietro
authors.initials: P
authors.lastname: Scalfaro
authors.forename: Geneviève
authors.initials: G
authors.lastname: Derumeaux
authors.forename: Michel
authors.initials: M
authors.lastname: Ovize
mesh_terms: D000208:Acute Disease; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009203:Myocardial Infarction / Q000503:physiopathology*; D010539:Permeability / Q000187:drug effects; D015427:Reperfusion Injury / Q000503:physiopathology*; D016019:Survival Analysis; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
chemical_list: D016572:Cyclosporine; D002118:Calcium; C499715:alisporivir