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

Abstract

Saotome M, Katoh H, Yaguchi Y, Tanaka T, Urushida T, Satoh H, Hayashi H. Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 296: H1125-H1132, 2009. First published February 6, 2009 doi:10.1152/ajpheart.00436.2008.-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 M] 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 2O2 (2 M) significantly improved the postischemic recoveries in left ventricular developed pressure, intracellular phosphocreatine, and ATP levels. A specific mPTP inhibitor cyclosporin A (CsA; 0.2 M) canceled these H2O2-induced effects. In isolated permeabilized myocytes, H 2O2 (1 M) accelerated the calcein leakage from mitochondria in a CsA-sensitive manner, indicating the opening of mPTP by H 2O2. However, H2O2 did not depolarize mitochondrial membrane potential (⌬⌿ m) even in the presence of oligomycin (F 1/F0 ATPase inhibitor; 1 M) and decreased mitochondrial Ca 2ϩ concentration ([Ca 2ϩ ]m) by accelerating the mitochondrial Ca 2ϩ 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 [Ca 2ϩ ]m without the change in ⌬⌿m might be a possible mechanism for the protection. energy metabolism; nuclear magnetic resonance spectroscopy; permeabilized myocytes; mitochondrial calcium ALTHOUGH THE GENERATION OF reactive oxygen species (ROS; e.g., superoxide, hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals) are well-known factors leading to ischemia-reperfusion (I/R) injury, it has also been reported that ROS participated in ischemic preconditioning (IPC) and served as an ameliorating cardioprotective substrate against I/R injury (5,26,29). The generation of ROS during brief and repetitive I/R is suggested to be a possible trigger for the initiation of IPC. However, despite previous intensive efforts, the precise mechanisms of endogenous ROS-mediated cardioprotection and how it mimics the IPC still remained elusive.Mitochondria have been identified as the target organelle responsible for the cell injury during I/R, since mitochondria are closely involved in a process of necrotic and apoptotic cell death through the mitochondrial permeability transition pore (mPTP) opening (14,21,24). The opening and clo...

Protective Role of Transient Pore Openings in Calcium Handling by Cardiac Mitochondria

“…This work was also supported by the Laubisch and Kawata Endowments. also found that when transient mPTP openings are induced by Ca 2ϩ loading, mitochondrial ROS production increases markedly, which may provide a link between loss of mPTP function and loss of cardioprotection when hearts are exposed to mPTP blockers during PC episodes (6,14,15).…”

“…These mice had elevated mitochondrial Ca 2ϩ content, suggesting a defect in mitochondrial Ca 2ϩ handling related to loss of mPTP function, with associated metabolic abnormalities. Second, whereas CsA given during prolonged ischemia reduces I/R injury (7), paradoxically, CsA (or sanglifehrin A) administered during ischemic or pharmacologic PC episodes blocks cardioprotection (6,14,15). This finding is reminiscent of reactive oxygen species (ROS), in which ROS scavengers given during prolonged ischemia reduce I/R injury, but ROS scavengers given during ischemic or pharmacologic PC episodes block cardioprotection (16).…”

Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures

“…Originally, VDAC was considered to be a crucial component of this canal but was ruled out later because the intrinsic apoptotic pathway was also induced in VDAC knockout mice (13). Currently, Halestrap et al (56) propose that mPTP is composed of adenine nucleotide translocase, mitochondrial phosphate carrier, and their regulator cyclophilin-D. Ca 2ϩ overload (57) or ROS (175) is crucial to open the pore that enables small molecules to pass between the mitochondrial matrix and cytosol, allowing for an H ϩ influx into mitochondria. This cancels the membrane potential across the mitochondrial membrane and results in mitochondrial swelling and subsequent apoptotic changes (66).…”

Retracted: Activation of Akt Rescues Endoplasmic Reticulum Stress-Impaired Murine Cardiac Contractile Function via Glycogen Synthase Kinase-3β-Mediated Suppression of Mitochondrial Permeation Pore Opening

“…Akt activation and TUDCA themselves did not exhibit any effect on mitochondrial membrane potential and NAD + content. To further evaluate the role of mPTP opening and GSK3b in ER stress-induced mitochondrial damage, cardiomyocytes from WT mice were treated with tunicamycin (3 lg/ml) for 5-6 h in the absence or presence of the mPTP inhibitor cyclosporin A (200 nM) (41) or the GSK3b inhibitor SB216763 (10 lM) (13) before the assessment of mitochondrial function. Intriguingly, both cyclosporin A and SB216763 were capable of preventing tunicamycin-induced loss of …”

“…To further evaluate the role of GSK3b and mPTP opening in ER stress-induced cardiac contractile dysfunction, murine cardiomyocytes from WT mice were treated with tunicamycin (3 lg/ml) for 5-6 h in the absence or presence of the mPTP inhibitor cyclosporine A (200 nM) (41) or the GSK3b inhibitor SB216763 (10 lM) (13) before assessment of cardiomyocyte mechanical function. The ER stress chaperon TUDCA (500 lM) was used as a positive control (11).…”