Abstract
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.
Highlights
Coronary artery disease (CAD) and acute myocardial infarction are two of the major causes of death worldwide
Our findings demonstrate that the cardioprotective effect of intermittent high-altitude (IHA) hypoxia against I/R injury is mediated via ZFP580, a downstream target of ERK1/2 signaling with anti-apoptotic roles in myocardial cells
Ethics statement All animals used in this study received humane care in compliance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH, publication number 85–23, revised 1996, http://grants.nih.gov/ grants/olaw/olaw.htm), and all the protocols were approved by the Animal Subjects Committee of the Academy of Military Medical Sciences, Beijing, China
Summary
Coronary artery disease (CAD) and acute myocardial infarction are two of the major causes of death worldwide. The high mortality rates associated with these diseases reflect a lack of effective strategies to reduce ischemia–reperfusion (I/R) injury. A number of these proteins are involved in endogenous cardioprotection against myocardial I/R injury. The fusion protein EGFP-ZNF580 is localized in the nuclei of MGC803 and HEK293 cell lines [4]. These data suggest that ZNF580 is a C2H2-type nuclear transcription factor. ZFP580 is a novel C2H2 type zinc-finger transcription factor recently identified by our laboratory. The aim of this study was to elucidate whether ZFP580 is involved in the cardioprotective effects of intermittent high-altitude (IHA) hypoxia against myocardial ischemiareperfusion (I/R) injury
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