期刊
CIRCULATION RESEARCH
卷 98, 期 10, 页码 1314-1322出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000222418.99976.1d
关键词
ATP; oxygen; proteasome; antioxidants; cell adaptation
资金
- NHLBI NIH HHS [5F32HL071421, P01-HL73641, F32 HL071421] Funding Source: Medline
We set out to determine whether cellular hypoxia, via mitochondrial reactive oxygen species, promotes Na, K-ATPase degradation via the ubiquitin-conjugating system. Cells exposed to 1.5% O-2 had a decrease in Na, K-ATPase activity and oxygen consumption. The total cell pool of alpha 1 Na, K-ATPase protein decreased on exposure to 1.5% O-2 for 30 hours, whereas the plasma membrane Na, K-ATPase was 50% degraded after 2 hours of hypoxia, which was prevented by lysosome and proteasome inhibitors. When Chinese hamster ovary cells that exhibit a temperature-sensitive defect in E1 ubiquitin conjugation enzyme were incubated at 40 degrees C and 1.5% O-2, the degradation of the alpha 1 Na, K-ATPase was prevented. Exogenous reactive oxygen species increased the plasma membrane Na, K-ATPase degradation, whereas, in mitochondrial DNA deficient rho(0) cells and in cells transfected with small interfering RNA against Rieske iron sulfur protein, the hypoxia-mediated Na, K-ATPase degradation was prevented. The catalase/superoxide dismutase (SOD) mimetic (EUK-134) and glutathione peroxidase overexpression prevented the hypoxia-mediated Na, KATPase degradation and overexpression of SOD1, but not SOD2, partially inhibited the Na+ pump degradation. Accordingly, we provide evidence that during hypoxia, mitochondrial reactive oxygen species are necessary to degrade the plasma membrane Na, K-ATPase via the ubiquitin- conjugating system.
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