Mitochondrial energy metabolism plays a critical role in the cardioprotection afforded by intermittent hypobaric hypoxia

Wang, Zhihua; Cai, Xiaolong; Wu, Lan; Yu, Zhuang; Liu, Jinlong; Zhou, Zhao-Nian; Liu, Jiankang; Yang, Huang‐Tian

doi:10.1113/expphysiol.2012.065102

Cited by 23 publications

(19 citation statements)

References 48 publications

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“…Additionally, ATP synthase participates in mitochondrial protein import (Martin et al, 1991). It has been shown in rats that mitochondrial ATP synthase inhibition adversely impacts mitochondrial membrane potential (Wang et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos

Robinson

Dumas

Ali

et al. 2018

Neurotoxicology and Teratology

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Ketamine, a phencyclidine derivative, is an antagonist of the Ca2+-permeable N-methyl-D-aspartate (NMDA)-type glutamate receptors. It is a pediatric anesthetic and has been implicated in developmental neurotoxicity. Ketamine has also been shown to deplete ATP in mammalian cells. Our previous studies showed that acetyl L-carnitine (ALCAR) prevented ketamine-induced cardiotoxicity and neurotoxicity in zebrafish embryos. Based on our finding that ALCAR’s protective effect was blunted by oligomycin A, an inhibitor of ATP synthase, we further investigated the effects of ketamine and ALCAR on ATP levels, mitochondria and ATP synthase in zebrafish embryos. The results demonstrated that ketamine reduced ATP levels in the embryos but not in the presence of ALCAR. Ketamine reduced total mitochondrial protein levels and mitochondrial potential, which were prevented with ALCAR co-treatment. To determine the cause of ketamine-induced ATP deficiency, we explored the status of ATP synthase. The results showed that a subunit of ATP synthase, atp5α1, was transcriptionally down-regulated by ketamine, but not in the presence of ALCAR, although ketamine caused a significant upregulation in another ATP synthase subunit, atp5β and total ATP synthase protein levels. Most of the ATP generated by heart mitochondria are utilized for its contraction and relaxation. Ketamine-treated embryos showed abnormal heart structure, which was abolished with ALCAR co-treatment. This study offers evidence for a potential mechanism by which ketamine could cause ATP deficiency mediated by mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos

Robinson

Dumas

Ali

et al. 2018

Neurotoxicology and Teratology

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“…At odds with the present investigation, in that study rats did not experience any significant change in body mass nor improved baseline myocardial performance. Whereas those Authors focused into the post-conditioning-like effects led by IH addressing the role of mitochondria in generating sub-lethal doses of ROS early at the reperfusion after ischemia in Langendorff-perfused hearts [26], here we focus into the pre-conditioning effects of IH by addressing the role of a number of signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia

et al. 2013

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BackgroundExposure to intermittent hypoxia (IH) may enhance cardiac function and protects heart against ischemia-reperfusion (I/R) injury. To elucidate the underlying mechanisms, we developed a cardioprotective IH model that was characterized at hemodynamic, biochemical and molecular levels.MethodsMice were exposed to 4 daily IH cycles (each composed of 2-min at 6-8% O2 followed by 3-min reoxygenation for 5 times) for 14 days, with normoxic mice as controls. Mice were then anesthetized and subdivided in various subgroups for analysis of contractility (pressure-volume loop), morphology, biochemistry or resistance to I/R (30-min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion and measurement of the area at risk and infarct size). In some mice, the phosphatidylinositide 3-kinase (PI3K) inhibitor wortmannin was administered (24 µg/kg ip) 15 min before LAD.ResultsWe found that IH did not induce myocardial hypertrophy; rather both contractility and cardiac function improved with greater number of capillaries per unit volume and greater expression of VEGF-R2, but not of VEGF. Besides increasing the phosphorylation of protein kinase B (Akt) and the endothelial isoform of NO synthase with respect to control, IH reduced the infarct size and post-LAD proteins carbonylation, index of oxidative damage. Administration of wortmannin reduced the level of Akt phosphorylation and worsened the infarct size.ConclusionWe conclude that the PI3K/Akt pathway is crucial for IH-induced cardioprotection and may represent a viable target to reduce myocardial I/R injury.

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“…The precise mechanism by which IHA hypoxia has protective effects against myocardial I/R injury is not clear. Several studies have reported that the protective effects of long-term chronic hypoxia as well as short-lived HPC, including both early and delayed forms, against acute I/R injury are related to the expression and/or activation of regulatory proteins [16]–[18]. In this study, we found that ZFP580 mRNA and protein expression levels in ischemic myocardium or H9c2 myocardial cells were significantly increased by I/R and remained at high levels during the early-phase of reperfusion (within 2 h after reperfusion or reoxygenation).…”

Section: Discussionmentioning

confidence: 99%

ZFP580, a Novel Zinc-Finger Transcription Factor, Is Involved in Cardioprotection of Intermittent High-Altitude Hypoxia against Myocardial Ischemia-Reperfusion Injury

Meng

Zhang

et al. 2014

PLoS ONE

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BackgroundZFP580 is a novel C2H2 type zinc-finger transcription factor recently identified by our laboratory. We previously showed that ZFP580 may be involved in cell survival and growth. The aim of this study was to elucidate whether ZFP580 is involved in the cardioprotective effects of intermittent high-altitude (IHA) hypoxia against myocardial ischemia-reperfusion (I/R) injury.Methods and ResultsAfter rats were subjected to myocardial ischemia for 30 min followed by reperfusion, ZFP580 expression in the left ventricle was measured. ZFP580 protein expression was found to be up-regulated within 1 h and decreased at 2 h after reperfusion. Comparing normoxic and IHA hypoxia-adapted rats (5000 m, 6 h day−1, 6 weeks) following I/R injury (30 min ischemia and 2 h reperfusion), we found that adaptation to IHA hypoxia attenuated infarct size and plasma leakage of lactate dehydrogenase and creatine kinase-MB. In addition, ZFP580 expression in the myocardium was up-regulated by IHA hypoxia. Consistent with this result, ZFP580 expression was found to be significantly increased in cultured H9c2 myocardial cells in the hypoxic preconditioning group compared with those in the control group following simulated I/R injury (3 h simulated ischemic hypoxia and 2 h reoxygenation). To determine the role of ZFP580 in apoptosis, lentivirus-mediated gene transfection was performed in H9c2 cells 72 h prior to simulated I/R exposure. The results showed that ZFP580 overexpression significantly inhibited I/R-induced apoptosis and caspase-3 activation. H9c2 cells were pretreated with or without PD98059, an inhibitor of ERK1/2 phosphorylation, and Western blot results showed that PD98059 (10 µM) markedly suppressed I/R-induced up-regulation of ZFP580 expression.ConclusionsOur findings demonstrate that the cardioprotective effect of IHA hypoxia against I/R injury is mediated via ZFP580, a downstream target of ERK1/2 signaling with anti-apoptotic roles in myocardial cells.

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Mitochondrial energy metabolism plays a critical role in the cardioprotection afforded by intermittent hypobaric hypoxia

Abstract: Intermittent hypobaric hypoxia (IHH) is an effective protective strategy against myocardial ischaemia-reperfusion (I/R

Cited by 23 publications

References 48 publications

Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos

Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos

Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia

ZFP580, a Novel Zinc-Finger Transcription Factor, Is Involved in Cardioprotection of Intermittent High-Altitude Hypoxia against Myocardial Ischemia-Reperfusion Injury

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