Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 106 (4): 1199-1204

Copyright © 2009 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL 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 www.pnas.org/cgi/content/full/0811018106/DCSupplemental.

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

© 2009 by The National Academy of Sciences of the USA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Mutual antagonism between hypoxia-inducible factors 1{alpha} and 2{alpha} regulates oxygen sensing and cardio-respiratory homeostasis.
G. Yuan, Y.-J. Peng, V. D. Reddy, V. V. Makarenko, J. Nanduri, S. A. Khan, J. A. Garcia, G. K. Kumar, G. L. Semenza, and N. R. Prabhakar (2013)
PNAS 110, E1788-E1796
   Abstract »    Full Text »    PDF »
Sensing hypoxia: physiology, genetics and epigenetics.
N. R. Prabhakar (2013)
J. Physiol. 591, 2245-2257
   Abstract »    Full Text »    PDF »
Pseudomonas aeruginosa Alkyl Quinolones Repress Hypoxia-Inducible Factor 1 (HIF-1) Signaling through HIF-1{alpha} Degradation.
C. Legendre, F. J. Reen, M. J. Mooij, G. P. McGlacken, C. Adams, and F. O'Gara (2012)
Infect. Immun. 80, 3985-3992
   Abstract »    Full Text »    PDF »
Sympatho-adrenal activation by chronic intermittent hypoxia.
N. R. Prabhakar, G. K. Kumar, and Y.-J. Peng (2012)
J Appl Physiol 113, 1304-1310
   Abstract »    Full Text »    PDF »
Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2.
N. R. Prabhakar and G. L. Semenza (2012)
Physiol Rev 92, 967-1003
   Abstract »    Full Text »    PDF »
Chronic nicotine induces hypoxia inducible factor-2{alpha} in perinatal rat adrenal chromaffin cells: role in transcriptional upregulation of KATP channel subunit Kir6.2.
S. Salman, S. T. Brown, and C. A. Nurse (2012)
Am J Physiol Cell Physiol 302, C1531-C1538
   Abstract »    Full Text »    PDF »
Effects of different acute hypoxic regimens on tissue oxygen profiles and metabolic outcomes.
C. Reinke, S. Bevans-Fonti, L. F. Drager, M.-K. Shin, and V. Y. Polotsky (2011)
J Appl Physiol 111, 881-890
   Abstract »    Full Text »    PDF »
Hypoxia inducible factor 1 links fast-patterned muscle activity and fast muscle phenotype in rats.
I. G. Lunde, S. L. Anton, J. C. Bruusgaard, Z. A. Rana, S. Ellefsen, and K. Gundersen (2011)
J. Physiol. 589, 1443-1454
   Abstract »    Full Text »    PDF »
Hypoxia-inducible factor 2{alpha} (HIF-2{alpha}) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension.
Y.-J. Peng, J. Nanduri, S. A. Khan, G. Yuan, N. Wang, B. Kinsman, D. R. Vaddi, G. K. Kumar, J. A. Garcia, G. L. Semenza, et al. (2011)
PNAS 108, 3065-3070
   Abstract »    Full Text »    PDF »
NADPH Oxidase-Dependent Regulation of T-Type Ca2+ Channels and Ryanodine Receptors Mediate the Augmented Exocytosis of Catecholamines from Intermittent Hypoxia-Treated Neonatal Rat Chromaffin Cells.
D. Souvannakitti, J. Nanduri, G. Yuan, G. K. Kumar, A. P. Fox, and N. R. Prabhakar (2010)
J. Neurosci. 30, 10763-10772
   Abstract »    Full Text »    PDF »
Neonatal intermittent hypoxia impairs neuronal nicotinic receptor expression and function in adrenal chromaffin cells.
D. Souvannakitti, B. Kuri, G. Yuan, A. Pawar, G. K. Kumar, C. Smith, A. P. Fox, and N. R. Prabhakar (2010)
Am J Physiol Cell Physiol 299, C381-C388
   Abstract »    Full Text »    PDF »
Physical Activity Attenuates Intermittent Hypoxia-induced Spatial Learning Deficits and Oxidative Stress.
D. Gozal, D. Nair, and A. D. Goldbart (2010)
182, 104-112
   Abstract »    Full Text »    PDF »
Selective Inhibition of Hypoxia-Inducible Factor (HIF) Prolyl-Hydroxylase 1 Mediates Neuroprotection against Normoxic Oxidative Death via HIF- and CREB-Independent Pathways.
A. Siddiq, L. R. Aminova, C. M. Troy, K. Suh, Z. Messer, G. L. Semenza, and R. R. Ratan (2009)
J. Neurosci. 29, 8828-8838
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882