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.

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

“…C57BL/6 J (male, 8-10 weeks old) were anesthetized by intraperitoneal mixture of 70 mg/kg pentobarbital sodium and 0.1 mg/kg buprenorphine as described previously. 7,[38][39][40] The animals were orally intubated, ventilated and body temperature was maintained at 37°C. A left thoracotomy was performed in the fourth intercostal space.…”

“…Myocardial infarct size was then determined by triphenyltetrazolium staining as described previously. 7,[38][39][40] Statistical analysis. Data are presented as mean ± S.E.M., unless otherwise specified.…”

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

“…Interestingly, in this same study, delaying NIM811 administration by 12 h following injury was effective in preventing cytoskeletal degradation. Finally, NIM811 significantly reduced reperfusion injury following experimental acute myocardial infarction [94,96,99]. Collectively, the findings of these studies suggest that an approach that targets the mPTP can be generalized to several models of cell death.…”

“…Numerous experimental studies and clinical observations have demonstrated that the immunosuppressant cyclosporin A (CsA), which inhibits mPT and promotes mitochondrial function, may be of therapeutic benefit in the treatment of acute traumatic brain injury (TBI), SCI, cerebral ischemia, and reperfusion injury following acute myocardial infarction [94][95][96][97][98][99][100][101][102][103]. Phase I clinical trials for the acute treatment of severe TBI have been performed, and follow-up trials have been proposed [104].…”

Role of the c subunit of the FOATP synthase in mitochondrial permeability transition

“…68 involved in the acute loss of neurons and cardiomyocytes induced by ischemia/re-oxygenation and excitotoxicity. 23,[58][59][60] The molecular mechanisms that trigger the opening of the PTPC in these settings share a prominent oxidative component and the cytosolic accumulation of Ca 2+ ions, which de facto are tightly linked to each other. 61 During the last decades, several proteins have been suggested to constitute core components of the PTPC, including various isoforms of VDAC and ANT as well as CYPD, yet only the latter appears to be truly required for MPT in vivo.…”