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...
Among the several mechanisms proposed for ischemic preconditioning (IPC), generation of reactive oxygen species (ROS) is reported to be involved in the cardioprotective effects of IPC. The present study was designed to investigate whether repetitive exposure to hydrogen peroxide (H(2)O(2)) can protect the myocardium against subsequent ischemia/reperfusion injury, and whether the H(2)O(2)-induced cardioprotection is related to the preservation of energy metabolism. Langendorff-perfused rat hearts were exposed to two, 5 min episodes of IPC or to various concentrations of H(2)O(2) twice and then to 35 min global ischemia and 40 min reperfusion. Using (31)P nuclear magnetic resonance ((31)P-NMR) spectroscopy, cardiac phosphocreatine (PCr) and ATP and intracellular pH (pH(i)) were monitored. IPC and the treatment with 2 micromol/L H(2)O(2) significantly improved the post-ischemic recovery of left ventricular developed pressure (LVDP) and the PCr and ATP compared with those of the control ischemia/reperfusion (LVDP: 36.9 +/-7.4% of baseline in control hearts, 84.0+/-3.5% in IPC, 65.4+/-3.8% in H(2)O(2); PCr: 51.1+/-5.3% in control hearts, 81.4+/-5.5% in IPC, 81.7+/-5.2% in H(2)O(2); ATP: 12.3+/-1.6% in control hearts; 30.0+/-2.8% in IPC, 28.6+/-2.3% in H(2)O(2), mean +/- SE, p<0.05). However, lower (0.5 micromol/L) or higher (10 micromol/L) concentration of H(2)O (2) had no effect. There were significant linear correlations between mean LVDP and high-energy metabolites after 40 min reperfusion in H(2)O(2)-treated hearts. In IPC-treated hearts, the mean LVDP was greater than that in the 2 micromol/L H(2)O(2)-treated hearts under similar levels of high-energy metabolites. IPC also ameliorated intracellular acidification (6.38+/-0.03 in control hearts, 6.65+/-0.04 in IPC, p<0.05), but treatment with H(2)O(2) did not affect pH(i) during ischemia (6.40+/-0.05 in H(2)O(2)). In conclusion, H(2)O(2) had protective effects against ischemia/reperfusion injury and the effects were related to the preservation of energy metabolism. IPC could have additional protective mechanisms that are associated with the amelioration of intracellular acidosis during ischemia.
schemic preconditioning (IPC) is a phenomenon whereby brief intermittent periods of ischemia protect the myocardium against subsequent lethal ischemia. 1 Although the mechanisms responsible for IPC still remain elusive, several factors, such as adenosine, acetylcholine and opioids, which activate protein kinase C, have been implicated in the cardioprotective effect of IPC. 2 Recently, ATP-sensitive potassium (KATP) channels and reactive oxygen species (ROS), among the signaling pathways mediating IPC, have attracted considerable attention. Though the involvement of sarcolemmal KATP channels in IPC was first suggested, 3 subsequent studies have reported that mitochondrial KATP (mitoKATP) channels play a potential role for the cardioprotective effects of KATP channel openers. 4 More recent studies have indicated that the opening of mitoKATP channels induces cardioprotection by generating ROS, which may act as intracellular messengers. 5,6 It has been reported that pretreatment with mitoKATP channel openers 4 or exogenous H2O2 7,8 induces IPC-like protective effects, and that IPC-induced cardioprotection is antagonized by mitoKATP channel inhibitors 9,10 or ROS scavengers. 11,12 These findings support the hypothesis that IPC is mediated through the opening of mitoKATP channels and ROS production. Nevertheless, several investigators have argued against the contribution of mitoKATP channels [13][14][15]17 to IPC. The protective effects of IPC and the mitoKATP channel opener diazoxide (DZ) in whole heart models have been generally evaluated as reduced infarct size and improved contractile function during reperfusion. IPC also has beneficial effects on energy metabolism, such as reduced intracellular acidification during ischemia and postischemic preservation of high-energy phosphates. [18][19][20] Measurement of these parameters may reveal the difference in the cardioprotective mechanisms between IPC and DZ. Moreover, a comparison of IPC and DZ under the same experimental condition would minimize the discrepancy in the results caused by the experimental conditions and models used. However, few studies have compared the effects of IPC and DZ on energy metabolism under the same experimental conditions. Therefore, in the present study we investigated the involvement of the opening of mitoKATP channels and ROS production in IPC-and DZ-induced cardioprotection, using the mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD) and the antioxidant N-acetylcysteine (NAC), in perfused Background Recent studies have implicated the opening of mitochondrial KATP (mitoKATP) channels and the production of reactive oxygen species (ROS) in the cardioprotective mechanism of ischemic preconditioning (IPC). Methods and ResultsThe involvement of mitoKATP channels and ROS in the cardioprotective effects of both IPC and the mitoKATP channel opener diazoxide (DZ) was investigated in ischemic/reperfused rat hearts. The effects of IPC and DZ on myocardial high-energy phosphate concentrations and intracellular pH (pHi) were also examined using 31...
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