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1 Department of Physiology, UCLA, Los Angeles, CA, USA; Medicine/Cardiology, UCLA, Los Angeles, CA, USA
2 Medicine/Cardiology, UCLA, Los Angeles, CA, USA; Department of Physiology, UCLA, Los Angeles, CA, USA
3 Medicine/Cardiology, UCLA, Los Angeles, CA, USA
4 Department of Physiology, UCLA, Los Angeles, CA, USA
5 Medicine/Anesthesiology, UCLA, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: peipeiping{at}earthlink.net.
The mitochondrial permeability transition (MPT) pore has recently been implicated as a potential mediator of myocardial ischemic injury. Nitric oxide (NO) donors induce a powerful late phase of cardioprotection against ischemia/reperfusion injury, however, the cellular mechanisms involved are poorly understood. The role of the MPT pore as a target of cardioprotective signaling pathways activated by NO has never been explored in detail. Thus, mice were administered the NO donor DETA/NO (0.1 mg/kg x 4, i.v.) 24 h prior to a 30-min coronary artery occlusion followed by 24 h of reperfusion. Infarct size was significantly reduced in DETA/NO-treated mice (30±2% in treated mice vs. 50±2% in control; p<0.05), demonstrating a powerful cardioprotection. To examine the role of the MPT pore, mice were administered atractyloside (Atr, 25 mg/kg, i.v.), which induces ANT-dependent MPT, 20 min prior to ischemia. Atr blocked the infarct-sparing effects of DETA/NO (infarct size was 58±1% of risk region vs 30±2% in DETA/NO; p<0.05) while Atr alone had no effect. Mitochondria isolated from DETA/NOtreated mice exhibited increased resistance to Ca2+-induced swelling by 20µmol/L CaCl2 or by a higher concentration of 200µmol/L, suggesting that cardioprotection involves decreased propensity for MPT. Pre-incubation of mitochondria from control hearts with 30 nmol/L of the pore inhibitor Cyclosporin-A prevented swelling by 200µmol/L CaCl2, confirming that Ca2+ induces mitochondrial swelling via MPT. In accordance with the effects on infarct size, administration of Atr to the mouse significantly abrogated DETA/NO-induced protection against Ca2+-induced mitochondrial swelling. These phenotypic alterations were associated with an increase in the anti-apoptotic protein, Bcl-2, suggesting that the underlying mechanisms may involve inhibition of cell death by Bcl-2. These data suggest that a critical process during NO donor-induced cardioprotection is to prevent MPT pore opening, potentially via targeting of ANT.
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