Metabolism of Preconditioned Myocardium: Effect of Loss and Reinstatement of Cardioprotection

Jennings, Robert B.; Sebbag, Laurent; Schwartz, Lisa M.; Crago, Mark S.; Reimer, Keith A.

doi:10.1006/jmcc.2001.1425

Cited by 56 publications

(54 citation statements)

References 41 publications

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“…These preconditioning-activated regulatory events are associated with a mitochondrial bioenergetic phenotype displaying an enhanced capacity to maintain energetic balance after bioenergetic stress coupled to efficient oxygen consumption during basal respiration. The complex repertoire of mitochondrial regulatory phenotypic changes observed in our study are directly concordant with the paradigm of maintaining cellular ATP levels to delay myocyte death in ischemia/reperfusion injury 22 and may be a central component of the delayed preconditioning-induced cardioprotective program.…”

Section: Discussionsupporting

confidence: 78%

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

et al. 2004

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Background-Delayed ischemic preconditioning promotes cardioprotection via genomic reprogramming. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective program. Methods and Results-Preconditioning was induced by use of 3 episodes of 3-minute coronary artery occlusion separated by 5 minutes of reperfusion. Twenty-four hours later, infarct size was reduced by 58% after preconditioning compared with sham-operated controls (PϽ0.001). Cardiac mitochondria were isolated from sham and preconditioned rat hearts. Mitochondrial respiration and ATP production were similar between the groups; however, preconditioned mitochondria exhibit modest hyperpolarization of the inner mitochondrial membrane potential (Ն22% versus control, PϽ0.001).After 35-minute anoxia and reoxygenation, preconditioned mitochondria demonstrated a 191Ϯ12% improvement in ADP-sensitive respiration (Pϭ0.002) with preservation of electron-transfer-chain (ETC) activity versus controls. This augmented mitochondrial recovery was eradicated when preconditioning was abolished by the antioxidant 2-mercaptopropionyl glycine (2-MPG). These biochemical modulations appear to be regulated at the genomic level in that the expression of genes encoding rate-controlling complexes in the ETC was significantly upregulated in preconditioned myocardium, with a concordant induction of steady-state protein levels of cytochrome oxidase, cytochrome c, and adenine nucleotide translocase-1. 2-MPG abolished preconditioning induction of these transcripts. Moreover, transcripts of nuclear regulatory peptides known to orchestrate mitochondrial biogenesis, nuclear respiratory factor-1 and peroxisome-proliferator-activated receptor gamma coactivator 1␣, were significantly induced in preconditioned myocardium. Conclusions-Delayed preconditioned mitochondria display increased tolerance against anoxia-reoxygenation in association with modifications in mitochondrial bioenergetics, with concordant genomic induction of a mitochondrial energetic gene regulatory program. This program appears to be mediated by reactive oxygen species signaling.

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Section: Discussionsupporting

confidence: 78%

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

et al. 2004

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“…Mitochondrial ⌬⌿ is lower during ischemia, leading to reduced Ca 2ϩ accumulation (63,67), which has been identified as being important for cardioprotection (25,36). Jennings et al (26) have shown that adenine nucleotides are rapidly degraded during ischemia and that IPC retards the rate of degradation. This may be particularly important, because the cardiomyocyte cannot survive reperfusion if there is no ADP available to phosphorylate.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart

Santos

Kowaltowski

Laclau

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

203

141

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. Mechanisms by which opening the mitochondrial ATP-sensitive K ϩ channel protects the ischemic heart. Am J Physiol Heart Circ Physiol 283: H284-H295, 2002. First published February 14, 2002 10.1152/ajpheart. 00034.2002-Diazoxide opening of the mitochondrial ATPsensitive K ϩ (mitoKATP) channel protects the heart against ischemia-reperfusion injury by unknown mechanisms. We investigated the mechanisms by which mitoKATP channel opening may act as an end effector of cardioprotection in the perfused rat heart model, in permeabilized fibers, and in rat heart mitochondria. We show that diazoxide pretreatment preserves the normal low outer membrane permeability to nucleotides and cytochrome c and that these beneficial effects are abolished by the mitoKATP channel inhibitor 5-hydroxydecanoate. We hypothesize that an open mitoK ATP channel during ischemia maintains the tight structure of the intermembrane space that is required to preserve the normal low outer membrane permeability to ADP and ATP. This hypothesis is supported by findings in mitochondria showing that small decreases in intermembrane space volume, induced by either osmotic swelling or diazoxide, increased the half-saturation constant for ADP stimulation of respiration and sharply reduced ATP hydrolysis. These effects are proposed to lead to preservation of adenine nucleotides during ischemia and efficient energy transfer upon reperfusion. mitochondria; metabolism; creatine kinase; membrane transport; cytochrome c; ischemic preconditioning THERE IS NOW GENERAL AGREEMENT that the mitochondrial ATP-sensitive K ϩ (mitoK ATP ) channel plays a pivotal role in cardioprotection against ischemia-reperfusion injury (16,17,20,21,36,64); however, little is known about the mechanism of this protection. It has been proposed that mitoK ATP channel opening triggers protection by increasing the generation of reactive oxygen species (ROS) (13, 47), and this effect has now been demonstrated by several laboratories (10,13,44,57). We proposed that the mitoK ATP channel is also an end effector of protection (16), and many studies have confirmed that the mitoK ATP channel is required to be open during the ischemic phase (11,46,58,59,64). Thus the mitoK ATP channel is both a trigger and an end effector of cardioprotection, and these two roles are temporally and mechanistically distinct.We have previously suggested that cardioprotection by mitoK ATP channel opening is due in part to volume regulation, which serves to preserve the structurefunction of the intermembrane space (IMS) and the low permeability of the outer membrane to nucleotides (31). Nucleotide transport across the outer membrane occurs primarily through the voltage-dependent anion channel (VDAC) (2, 34, 49, 50). We hypothesize that VDAC permeability to nucleotides is regulated in part by IMS volume, which in turn is regulated by K ϩ flux across the inner membrane.This study focuses on the end effector mechanisms by which an open mitoK ATP channel protects the heart during ischemia and reperfusion. We show, in sapon...

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“…What type of changes in glycolysis could possibly be associated with protection against I/R injury? It has been reported that cardioprotection induced by preconditioning resulted in decreased anaerobic glycolysis and a decreased build-up of fructose-6-phosphate and lactate, despite normal or even elevated levels of glucose and glucose-6-phosphate during the sustained ischemia (Murry et al 1986;Jennings et al 2001;Vogt et al 2002). Thus preconditioning induced alterations in glycolysis that are localized just after the first step of glycolysis, i.e.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial hexokinase and cardioprotection of the intact heart

Zuurbier

Smeele

Eerbeek

2009

J Bioenerg Biomembr

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The interaction of hexokinase with mitochondria has emerged as a powerful mechanism in protecting many cell types against cell death. However, the role of mitochondrial hexokinase (mitoHK) in cardiac ischemia-reperfusion injury has as of yet received little attention. In this review we examine whether increased binding of hexokinase to the mitochondrion is also an integral component of cardioprotective signalling. We discuss observations in cardiac mitochondrial activation that directed us to the hypothesis of hexokinase cellular redistribution with reversible, cardioprotective ischemia, summarize the data showing that many cardioprotective interventions, such as ischemic preconditioning, insulin, morphine and volatile anesthetics, increase mitochondrial hexokinase binding within the intact heart, and discuss similarities between mitochondrial hexokinase association and ischemic preconditioning. Although most data indicate that mitochondrial hexokinase may indeed be an integral part of cardioprotection, a definitive proof for a causal relation between the amount of mitoHK and cardiac ischemia-reperfusion injury in the intact heart is eagerly awaited. When such relationship is indeed observed, the association of hexokinase with mitochondria will offer an opportunity to develop new therapies to combat ischemic cardiac diseases.

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Metabolism of Preconditioned Myocardium: Effect of Loss and Reinstatement of Cardioprotection

Cited by 56 publications

References 41 publications

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart

Mitochondrial hexokinase and cardioprotection of the intact heart

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Metabolism of Preconditioned Myocardium: Effect of Loss and Reinstatement of Cardioprotection

Cited by 56 publications

References 41 publications

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

Mechanisms by which opening the mitochondrial ATP- sensitive K+channel protects the ischemic heart

Mitochondrial hexokinase and cardioprotection of the intact heart

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Mechanisms by which opening the mitochondrial ATP- sensitive K⁺channel protects the ischemic heart