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Intermittent hypoxia degrades HIF-2 via calpains resulting in oxidative stress: Implications for recurrent apnea-induced morbidities
Shakil A. Khana,
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.
Intermittent hypoxia (IH) occurs in many pathological conditionsincluding recurrent apneas. Hypoxia-inducible factors (HIFs)1 and 2 mediate transcriptional responses to low O2. A previousstudy showed that HIF-1 mediates some of the IH-evoked physiologicalresponses. Because HIF-2 is an orthologue of HIF-1, we examinedthe effects of IH on HIF-2, the O2-regulated subunit expression,in pheochromocytoma 12 cell cultures. In contrast to the up-regulationof HIF-1, HIF-2 was down-regulated by IH. Similar down-regulationof HIF-2 was also seen in carotid bodies and adrenal medullaefrom IH-exposed rats. Inhibitors of calpain proteases (ALLM,ALLN) prevented IH-evoked degradation of HIF-2 whereas inhibitorsof prolyl hydroxylases or proteosome were ineffective. IH activatedcalpain proteases and down-regulated the endogenous calpaininhibitor calpastatin. IH-evoked HIF-2 degradation led to inhibitionof SOD2 transcription, resulting in oxidative stress. Over-expressionof transcriptionally active HIF-2 prevented IH-evoked oxidativestress and restored SOD2 activity. Systemic treatment of IH-exposedrats with ALLM rescued HIF-2 degradation and restored SOD2 activity,thereby preventing oxidative stress and hypertension. Theseobservations demonstrate that, unlike continuous hypoxia, IHleads to down-regulation of HIF-2 via a calpain-dependent signalingpathway and results in oxidative stress as well as autonomicmorbidities.
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.