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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/H1125    most recent 00436.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Saotome, M. Articles by Hayashi, H. Search for Related Content PubMed PubMed Citation Articles by Saotome, M. Articles by Hayashi, H.

Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia-reperfusion injury

Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine, Higashi-ku, Hamamatsu, Japan

Submitted 26 April 2008 ; accepted in final form 28 January 2009

Reactive oxygen species (ROS) production during ischemia-reperfusion (I/R) is thought to be a critical factor for myocardial injury. However, a small amount of ROS during the ischemic preconditioning (IPC) may provide a signal for cardioprotection. We have previously reported that the repetitive pretreatment of a small amount of ROS [hydrogen peroxide (H₂O₂), 2 µM] mimicked the IPC-induced cardioprotection in the Langendorff-perfused rat hearts. We further investigated the mechanisms of the ROS-induced cardioprotection against I/R injury and tested the hypothesis whether it could mediate the mitochondrial permeability transition pore (mPTP) opening. The Langendorff-perfused rat hearts were subjected to 35 min ischemia and 40 min reperfusion, and the pretreatment of H₂O₂ (2 µM) significantly improved the postischemic recoveries in left ventricular developed pressure, intracellular phosphocreatine, and ATP levels. A specific mPTP inhibitor cyclosporin A (CsA; 0.2 µM) canceled these H₂O₂-induced effects. In isolated permeabilized myocytes, H₂O₂ (1 µM) accelerated the calcein leakage from mitochondria in a CsA-sensitive manner, indicating the opening of mPTP by H₂O₂. However, H₂O₂ did not depolarize mitochondrial membrane potential (_m) even in the presence of oligomycin (F₁/F₀ ATPase inhibitor; 1 µM) and decreased mitochondrial Ca²⁺ concentration ([Ca²⁺]_m) by accelerating the mitochondrial Ca²⁺ extrusion via an mPTP. We conclude that the transient mPTP opening could be involved in the H₂O₂-induced cardioprotection against reperfusion injury, and the reduction of [Ca²⁺]_m without the change in _m might be a possible mechanism for the protection.

energy metabolism; nuclear magnetic resonance spectroscopy; permeabilized myocytes; mitochondrial calcium