ZFP580, a novel zinc-finger transcription factor, is involved in cardioprotection of intermittent high-altitude hypoxia against myocardial ischemia-reperfusion injury.
BACKGROUND
ZFP580 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.


RESULTS
After 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.


CONCLUSIONS
Our 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.
Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Tianjin, China; Department of Physiology and Pathophysiology, Logistics University of Chinese People's Armed Police Force, Tianjin, China.
Xiang-Yan
XY
Meng
Department of Physiology and Pathophysiology, Logistics University of Chinese People's Armed Police Force, Tianjin, China.
Hai-Long
HL
Yu
Department of Physiology and Pathophysiology, Logistics University of Chinese People's Armed Police Force, Tianjin, China.
Wen-Cheng
WC
Zhang
Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Tianjin, China.
Tian-Hui
TH
Wang
Department of Physiology and Pathophysiology, Logistics University of Chinese People's Armed Police Force, Tianjin, China.
Xia
X
Mai
Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Tianjin, China.
Hong-Tao
HT
Liu
Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard, Logistics University of Chinese People's Armed Police Forces, Tianjin, China.
Rui-Cheng
RC
Xu
D000222:Adaptation, Physiological / Q000502:physiology*; D000531:Altitude; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D052279:Creatine Kinase, MB Form / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D016335:Zinc Fingers / Q000502:physiology*
D014157:Transcription Factors; C000598274:ZFP580 protein, rat; D007770:L-Lactate Dehydrogenase; D052279:Creatine Kinase, MB Form