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PNAS 106 (4): 1199-1204

Copyright © 2009 by the National Academy of Sciences.


Intermittent hypoxia degrades HIF-2{alpha} via calpains resulting in oxidative stress: Implications for recurrent apnea-induced morbidities

Jayasri Nanduria, Ning Wanga, Guoxiang Yuana, Shakil A. Khana, Dangjai Souvannakittia, Ying-Jie Penga, Ganesh K. Kumara, Joseph A. Garciab,c, and Nanduri R. Prabhakara,1

aCenter for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637; bVeterans Affairs North Texas Healthcare System, Dallas, Texas 75216; and cDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Edited by Gregg L. Semenza, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 12, 2008

Received for publication October 30, 2008.

Abstract: Intermittent hypoxia (IH) occurs in many pathological conditions including recurrent apneas. Hypoxia-inducible factors (HIFs) 1 and 2 mediate transcriptional responses to low O2. A previous study showed that HIF-1 mediates some of the IH-evoked physiological responses. Because HIF-2{alpha} is an orthologue of HIF-1{alpha}, we examined the effects of IH on HIF-2{alpha}, the O2-regulated subunit expression, in pheochromocytoma 12 cell cultures. In contrast to the up-regulation of HIF-1{alpha}, HIF-2{alpha} was down-regulated by IH. Similar down-regulation of HIF-2{alpha} was also seen in carotid bodies and adrenal medullae from IH-exposed rats. Inhibitors of calpain proteases (ALLM, ALLN) prevented IH-evoked degradation of HIF-2{alpha} whereas inhibitors of prolyl hydroxylases or proteosome were ineffective. IH activated calpain proteases and down-regulated the endogenous calpain inhibitor calpastatin. IH-evoked HIF-2{alpha} degradation led to inhibition of SOD2 transcription, resulting in oxidative stress. Over-expression of transcriptionally active HIF-2{alpha} prevented IH-evoked oxidative stress and restored SOD2 activity. Systemic treatment of IH-exposed rats with ALLM rescued HIF-2{alpha} degradation and restored SOD2 activity, thereby preventing oxidative stress and hypertension. These observations demonstrate that, unlike continuous hypoxia, IH leads to down-regulation of HIF-2{alpha} via a calpain-dependent signaling pathway and results in oxidative stress as well as autonomic morbidities.

Key Words: calcium signaling • hypoxia inducible factors

Freely available online through the PNAS open access option.

Author contributions: J.N. and N.R.P. designed research; J.N., N.W., G.Y., S.A.K., D.S., Y.-J.P., and G.K.K. performed research; J.A.G. contributed new reagents/analytic tools; J.N., N.W., Y.-J.P., and G.K.K. analyzed data; and J.N., J.A.G., and N.R.P. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: nanduri{at}

© 2009 by The National Academy of Sciences of the USA

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