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Am J Physiol Cell Physiol 295: C1281-C1291, 2008. First published September 11, 2008; doi:10.1152/ajpcell.00550.2007
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CELLULAR AND MITOCHONDRIAL METABOLISM

Activation of Hsp90-eNOS and increased NO generation attenuate respiration of hypoxia-treated endothelial cells

Tennille Presley,1,2 Kaushik Vedam,3 Murugesan Velayutham,1,3 Jay L. Zweier,3 and Govindasamy Ilangovan1,2,3

1The Center for Biomedical EPR Spectroscopy and Imaging, 2Biophysics Program, and 3The Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute and The Ohio State University, Columbus, Ohio

Submitted 19 November 2007 ; accepted in final form 3 September 2008

Hypoxia induces various adoptive signaling in cells that can cause several physiological changes. In the present work, we have observed that exposure of bovine aortic endothelial cells (BAECs) to extreme hypoxia (1–5% O2) attenuates cellular respiration by a mechanism involving heat shock protein 90 (Hsp90) and endothelial nitric oxide (NO) synthase (eNOS), so that the cells are conditioned to consume less oxygen and survive in prolonged hypoxic conditions. BAECs, exposed to 1% O2, showed a reduced respiration compared with 21% O2-maintained cells. Western blot analysis showed an increase in the association of Hsp90-eNOS and enhanced NO generation on hypoxia exposure, whereas there was no significant accumulation of hypoxia-inducible factor-1{alpha} (HIF-1{alpha}). The addition of inhibitors of Hsp90, phosphatidylinositol 3-kinase, and NOS significantly alleviated this hypoxia-induced attenuation of respiration. Thus we conclude that hypoxia-induced excess NO and its derivatives such as ONOO– cause inhibition of the electron transport chain and attenuate O2 demand, leading to cell survival at extreme hypoxia. More importantly, such an attenuation is found to be independent of HIF-1{alpha}, which is otherwise thought to be the key regulator of respiration in hypoxia-exposed cells, through a nonphosphorylative glycolytic pathway. The present mechanistic insight will be helpful to understand the difference in the magnitude of endothelial dysfunction.

oxygen; electron paramagnetic resonance oximetry; heat shock protein 90; endothelial nitric oxide synthase


Address for reprint requests and other correspondence: G. Ilangovan, Rm. 392, Biomedical Research Tower, Ohio State Univ., 420 West 12th Ave., Columbus, OH 43210 (e-mail: govindasamy.ilangovan{at}osumc.edu)






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