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Hypoxia-induced apoptosis of mouse spermatocytes is mediated by HIF-1α through a death receptor pathway and a mitochondrial pathway.

Authors
  • Yin, Jun1
  • Ni, Bing1
  • Liao, Wei-Gong1
  • Gao, Yu-Qi2
  • 1 Department of Pathophysiology and High Altitude Pathology/Key Laboratory of High Altitude Environment Medicine (Third Military Medical University), Ministry of Education/Key Laboratory of High Altitude Medicine, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, PR China. , (China)
  • 2 Institute of Medicine and Hygienic Equipment for High Altitude Region/Key Laboratory of High Altitude Environment Medicine (Third Military Medical University), Ministry of Education/Key Laboratory of High Altitude Medicine, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, PR China. , (China)
Type
Published Article
Journal
Journal of Cellular Physiology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Feb 01, 2018
Volume
233
Issue
2
Pages
1146–1155
Identifiers
DOI: 10.1002/jcp.25974
PMID: 28444885
Source
Medline
Keywords
License
Unknown

Abstract

Hypoxia in vivo induces oligozoospermia, azoospermia, and degeneration of the germinal epithelium, but the underlying molecular mechanism of this induction is not fully clarified. The aim of this study was to investigate the role of the death receptor pathway and the mitochondrial pathway in hypoxia-induced apoptosis of mouse GC-2spd (GC-2) cells and the relationship between HIF-1α and apoptosis of GC-2 cells induced by hypoxia. GC-2 cells were subjected to 1% oxygen for 48 hr. Apoptosis was detected by flow cytometry, TUNEL staining, LDH, caspase-3/8/9 in the absence and presence of HIF-1α siRNA. The protein levels of apoptosis-related markers were determined by Western blot in the presence and absence of HIF-1α siRNA. Mitochondrial transmembrane potential change was observed by in situ JC-1 staining. Cell viability was assessed upon treatment of caspase-8 and 9 inhibitors. The results indicated that hypoxia at 1% oxygen for 48 hr induced apoptosis of GC-2 cells. A prolonged exposure of GC-2 cells to hypoxic conditions caused downregulation of c-FLIP, Dc R2 and Bcl-2 and upregulation of DR5 , TRAIL, Fas, p53, and Bax, with an overproduction of caspase-3/8/9. Moreover, hypoxia at this level had an effect on mitochondrial depolarization. In addition, specific inhibitors of caspase-8/9 partially suppressed hypoxia-induced GC-2 cell apoptosis, and the anti-apoptotic effects of the caspase inhibitors were additive. Of note, HIF-1α knockdown attenuated hypoxia and induced apoptosis of GC-2 cells. In conclusion, our data suggest that the death receptor pathway and mitochondrial pathway, which are likely mediated by HIF-1α, contribute to hypoxia-induced GC-2 cell apoptosis.

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