Direct activation of mitochondrial KATP channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts

Tani, Masato

doi:10.1016/s0008-6363(00)00240-6

Cited by 80 publications

(52 citation statements)

References 36 publications

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“…Isolated, buffer-perfused hearts from 24-mo-old Fischer 344 rats sustain greater myocardial injury after ischemia and reperfusion than hearts from 6-mo-old adult controls (82,93,94,134). Unfortunately, IPC provides minimal cardioprotection in the aged rat (1,133,134) and human hearts (78). Thus, a potentially useful approach to protect aged myocardium is ineffective, and highlights the importance of considering other approaches to modulate mitochondrial oxidative metabolism to protect the aged heart.…”

Section: Increased Injury In the Aged Heart During Ischemia And Repermentioning

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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Section: Increased Injury In the Aged Heart During Ischemia And Repermentioning

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

View full text Add to dashboard Cite

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“…Investigators have unmasked other relevant aspects of impaired signaling. Tani and colleagues (208,212) provided evidence of failed activation and translocation of PKC in aged hearts. Przyklenk et al (172) have shown that age selectively alters the nature of protective PKC signaling, with Precon responses PKC ε dependent in young but not aged myocardium.…”

Section: Age and Disease Dependence Of Cardioprotectionmentioning

confidence: 99%

Clinical cardioprotection and the value of conditioning responses

Peart

Headrick²

2009

American Journal of Physiology-Heart and Circulatory Physiology

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Adjunctive cardioprotective strategies for ameliorating the reversible and irreversible injuries with ischemia-reperfusion (I/R) are highly desirable. However, after decades of research, the promise of clinical cardioprotection from I/R injury remains poorly realized. This may arise from the challenges of trialing and effectively translating experimental findings from laboratory models to patients. One can additionally consider whether features of the more heavily focused upon candidates could limit or preclude therapeutic utility and thus whether we might shift attention to alternate strategies. The phenomena of preconditioning and postconditioning have proven fertile in identification of experimental means of cardioprotection and are the most intensely interrogated responses in the field. However, there is evidence these processes, which share common molecular signaling elements and end effectors, may be poor choices for clinical exploitation. This includes evidence of age dependence, limiting efficacy in target aged or senescent hearts; refractoriness to conditioning stimuli in diseased myocardium; interference from a variety of relevant pharmaceuticals; inadvertent induction of these responses by prior ischemia or commonly used drugs, precluding further benefit; and sex dependence of protective signaling. This review focuses on these features, raising questions about current research strategies, and the suitability of these widely studied phenomena as rational candidates for clinical translation.

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“…The abrogating effect of aging on myocardial protection through ischemic preconditioning has also been stressed in many experimental studies [10,11]. However, it must be admitted that the full elucidation of how this mechanism operates is still lacking.…”

Section: Patient Statusmentioning

confidence: 99%

Myocardial protection in man—from research concept to clinical practice

Cokkinos

Pantos

2007

Heart Fail Rev

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Myocardial protection aims at preventing myocardial tissue loss: (a) In the acute stage, i.e., during primary angioplasty in acute myocardial infarction. In this setup, the attenuation of reperfusion injury is the main target. As a "mechanical" means, post-conditioning has already been tried in man with encouraging results. Pharmacologic interventions that could be of promise are statins, insulin, peptide hormones, including erythropoietin, fibroblast growth factor, and many others. (b) The patient with chronic coronary artery disease offers another paradigm, with the target of avoidance of further myocyte loss through apoptosis and inflammation. Various pharmacologic agents may prove useful in this context, together with exercise and "mechanical" improvement of cardiac function with attenuation of myocardial stretch, which by itself is a noxious influence. A continuous effort toward acute and chronically preserving myocardial integrity is a concept concerning both the researcher and the clinician.

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Direct activation of mitochondrial KATP channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts

Cited by 80 publications

References 36 publications

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

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

Clinical cardioprotection and the value of conditioning responses

Myocardial protection in man—from research concept to clinical practice

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