Protection by verapamil of mitochondrial glutathione equilibrium and phospholipid changes during reperfusion of ischemic canine myocardium.

Kajiyama, Kiminori; Pauly, Daniel F.; Hughes, Helen MacGill; Yoon, Seung Boo; Entman, Mark L.; McMillin-Wood, Jeanie B.

doi:10.1161/01.res.61.2.301

Cited by 50 publications

(19 citation statements)

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“…A number of factors have been suggested to contribute to the mitochondrial damage associated with ischemia and reperfusion. Cumulative evidence supports the fact that oxygen free radicals have been involved in the development of various pathological conditions, including ischemia-reperfusion-induced mitochondrial damage [5,20]. Generation of oxygen free radicals was reported to be enhanced during reperfusion.…”

Section: Discussionmentioning

confidence: 81%

The effects of a high dose of ascorbate on ischemia-reperfusion-induced mitochondrial dysfunction in canine hearts

et al. 1992

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The cardioprotective effects of a high dose of ascorbate on ischemia-reperfusion-induced myocardial damage were investigated using open chest anesthetized dogs. Two-hour occlusion of the left anterior descending coronary artery (LAD) induced mitochondrial dysfunction with a depletion of mitochondrial glutathione (GSH) concentration. Two-hour LAD occlusion followed by 1-h reperfusion worsened the ischemia-induced mitochondrial dysfunction together with a marked depletion of mitochondrial GSH concentration. Ascorbate reduced the mitochondrial dysfunction and prevented the depletion of mitochondrial GSH concentration after 2-h LAD occlusion and 1-h reperfusion. Activities of mitochondrial glutathione peroxidase and glutathione reductase did not change significantly in each group. Administration of ascorbate also prevented reperfusion arrhythmias without affecting blood pressure or heart rate. These results suggest that coronary reperfusion induces mitochondrial dysfunction and a depletion of mitochondrial GSH concentration, and that a high dose of ascorbate prevents reperfusion damage.

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Section: Discussionmentioning

confidence: 81%

The effects of a high dose of ascorbate on ischemia-reperfusion-induced mitochondrial dysfunction in canine hearts

et al. 1992

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“…Mitochondria sustain progressive damage during myocardial ischemia (45, 47,69,79,90,113,120,126,140), including to the electron transport chain (10, 45, 47,83,90,113,120,143). Ten to twenty minutes of ischemia decreases complex I activity (47, 120).…”

Section: Mitochondria As Targets Of Damage During Ischemiamentioning

confidence: 99%

“…Thus SSM are more susceptible to calcium overload-mediated cytochrome c release and mitochondrial damage compared with IFM (108). Progression of ischemic damage is more rapid in SSM than in IFM (45, 69,90,126,140).…”

Section: Mitochondria As Targets Of Damage During Ischemiamentioning

confidence: 99%

Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion

Chen

Camara

Stowe

et al. 2007

American Journal of Physiology-Cell Physiology

239

240

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Chen Q, Camara AK, Stowe DF, Hoppel CL, Lesnefsky EJ. Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am J Physiol Cell Physiol 292: C137-C147, 2007. First published September 13, 2006; doi:10.1152/ajpcell.00270.2006.-Mitochondria are increasingly recognized as lynchpins in the evolution of cardiac injury during ischemia and reperfusion. This review addresses the emerging concept that modulation of mitochondrial respiration during and immediately following an episode of ischemia can attenuate the extent of myocardial injury. The blockade of electron transport and the partial uncoupling of respiration are two mechanisms whereby manipulation of mitochondrial metabolism during ischemia decreases cardiac injury. Although protection by inhibition of electron transport or uncoupling of respiration initially appears to be counterintuitive, the continuation of mitochondrial oxidative phosphorylation in the pathological milieu of ischemia generates reactive oxygen species, mitochondrial calcium overload, and the release of cytochrome c. The initial target of these deleterious mitochondrial-driven processes is the mitochondria themselves. Consequences to the cardiomyocyte, in turn, include oxidative damage, the onset of mitochondrial permeability transition, and activation of apoptotic cascades, all favoring cardiomyocyte death. Ischemia-induced mitochondrial damage carried forward into reperfusion further amplifies these mechanisms of mitochondrial-driven myocyte injury. Interruption of mitochondrial respiration during early reperfusion by pharmacologic blockade of electron transport or even recurrent hypoxia or brief ischemia paradoxically decreases cardiac injury. It increasingly appears that the cardioprotective paradigms of ischemic preconditioning and postconditioning utilize modulation of mitochondrial oxidative metabolism as a key effector mechanism. The initially counterintuitive approach to inhibit mitochondrial respiration provides a new cardioprotective paradigm to decrease cellular injury during both ischemia and reperfusion.cardiolipin; cytochrome c; complex I; cytochrome oxidase MITOCHONDRIA are both targets and sources of injury during cardiac ischemia and reperfusion. This review addresses the emerging concept that modulation of mitochondrial oxidative metabolism during ischemia or early reperfusion protects mitochondrial function and decreases myocardial cell death. Mitochondria contribute to their own damage during ischemia, since blockade of electron transport immediately before ischemia dramatically attenuates damage to mitochondrial electron transport, with preserved oxidative phosphorylation, retention of cytochrome c, and decreased release of reactive oxygen species (ROS). Ischemic preconditioning (IPC) leads to a partial uncoupling of mitochondrial respiration, resulting in decreased mitochondrial injury following subsequent sustained ischemia. A substantial portion of damage to mitochondrial electron transport and oxi...

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“…There are numerous oxidative stress-induced pathophysiologic conditions during which redox status and, in particular, the GSH/GSSG ratio is perturbed (43,(45)(46)(47). An important role for glutathione has been proposed for the pathogenesis of PD, where a decrease in GSH concentrations in the substantia nigra was observed in preclinical stages of the disease (48).…”

Section: Inactivation Of Idpm By Gssg-inactivation Of Idpm Withmentioning

confidence: 99%

Regulation of Mitochondrial NADP+-dependent Isocitrate Dehydrogenase Activity by Glutathionylation

Kil

Park

2005

Journal of Biological Chemistry

130

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Recently, we demonstrated that the control of mitochondrial redox balance and oxidative damage is one of the primary functions of mitochondrial NADP ؉ -dependent isocitrate dehydrogenase (IDPm). Because cysteine residue(s) in IDPm are susceptible to inactivation by a number of thiol-modifying reagents, we hypothesized that IDPm is likely a target for regulation by an oxidative mechanism, specifically glutathionylation. Oxidized glutathione led to enzyme inactivation with simultaneous formation of a mixed disulfide between glutathione and the cysteine residue(s) in IDPm, which was detected by immunoblotting with anti-GSH IgG. The inactivated IDPm was reactivated enzymatically by glutaredoxin2 in the presence of GSH, indicating that the inactivated form of IDPm is a glutathionyl mixed disulfide. Mass spectrometry and site-directed mutagenesis further confirmed that glutathionylation occurs to a Cys 269 of IDPm. The glutathionylated IDPm appeared to be significantly less susceptible than native protein to peptide fragmentation by reactive oxygen species and proteolytic digestion, suggesting that glutathionylation plays a protective role presumably through the structural alterations. HEK293 cells and intact respiring mitochondria treated with oxidants inducing GSH oxidation such as H 2 O 2 or diamide showed a decrease in IDPm activity and the accumulation of glutathionylated enzyme. Using immunoprecipitation with anti-IDPm IgG and immunoblotting with anti-GSH IgG, we were also able to purify and positively identify glutathionylated IDPm from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, a model for Parkinson's disease. The results of the current study indicate that IDPm activity appears to be modulated through enzymatic glutathionylation and deglutathionylation during oxidative stress.The initial cellular response to oxidative stress is often a reduction in the levels of GSH, which represents the major low molecular weight antioxidant in mammalian cells, and a corresponding increase of GSSG, the oxidized form of GSH (1-3). It is well established that GSH plays a central role in the cellular defense against oxidative damage (4). Thus, the oxidation of a limited amount of GSH to GSSG can dramatically change this ratio and affect the redox status within the cell.Under these conditions of moderate oxidative stress, thiol groups of intracellular proteins can be modified by the reversible formation of mixed disulfides between protein thiols and low molecular mass thiols such as GSH, a process known as S-glutathionylation (5). Glutathionylation, which is reversible by the actions of the enzyme glutaredoxin (thioltransferase) (6, 7), may serve as a means of protection by preventing the irreversible oxidation of cysteine to cysteine sulfinic and sulfonic acid.One proposed mechanism leading to protein glutathionylation in vivo is the thiol/disulfide exchange mechanism (8), which occurs when an oxidative insult changes the GSSG/GSH ratio and induces GSSG to bind to protein thiols. GSSG/GSH ratio is an indicator of...

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Protection by verapamil of mitochondrial glutathione equilibrium and phospholipid changes during reperfusion of ischemic canine myocardium.

Cited by 50 publications

References 49 publications

The effects of a high dose of ascorbate on ischemia-reperfusion-induced mitochondrial dysfunction in canine hearts

The effects of a high dose of ascorbate on ischemia-reperfusion-induced mitochondrial dysfunction in canine hearts

Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion

Regulation of Mitochondrial NADP+-dependent Isocitrate Dehydrogenase Activity by Glutathionylation

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