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

• Published in: American journal of physiology. Heart and circulatory physiology 2009-04, Vol.296 (4), p.H1125-H1132
• Main Authors: Saotome, Masao, Katoh, Hideki, Yaguchi, Yasuhiro, Tanaka, Takamitsu, Urushida, Tsuyoshi, Satoh, Hiroshi, Hayashi, Hideharu
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Cardiovascular disease; Chemical compounds; Cyclosporine - pharmacology; Fluoresceins - metabolism; Heart; Hydrogen Peroxide - pharmacology; Ions; Magnetic Resonance Spectroscopy; Male; Membrane Potential, Mitochondrial - drug effects; Membranes; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors; Mitochondrial Membrane Transport Proteins - drug effects; Mitochondrial Membrane Transport Proteins - metabolism; Myocardial Contraction - drug effects; Myocardium - cytology; Myocardium - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Permeability; Physiology; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - pharmacology; Reperfusion Injury - metabolism; Reperfusion Injury - prevention & control; Rodents; Ventricular Function, Left - drug effects
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00436.2008

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 (H 2 O 2 ), 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 H 2 O 2 (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 H 2 O 2 -induced effects. In isolated permeabilized myocytes, H 2 O 2 (1 µM) accelerated the calcein leakage from mitochondria in a CsA-sensitive manner, indicating the opening of mPTP by H 2 O 2 . However, H 2 O 2 did not depolarize mitochondrial membrane potential ( m ) even in the presence of oligomycin (F 1 /F 0 ATPase inhibitor; 1 µM) and decreased mitochondrial Ca 2+ concentration ([Ca 2+ ] m ) by accelerating the mitochondrial Ca 2+ extrusion via an mPTP. We conclude that the transient mPTP opening could be involved in the H 2 O 2 -induced cardioprotection against reperfusion injury, and the reduction of [Ca 2+ ] m without the change in m might be a possible mechanism for the protection. energy metabolism; nuclear magnetic resonance spectroscopy; permeabilized myocytes; mitochondrial calcium Address for reprint requests and other correspondence: M. Saotome, Division of Cardiology, Internal Medicine III, Hamamatsu Univ. School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan (e-mail: msaotome{at}hama-med.ac.jp )