Intermittent hypoxia degrades HIF-2alpha via calpains resulting in oxidative stress: implications for recurrent apnea-induced morbidities.
Intermittent hypoxia (IH) occurs in many pathological conditions including recurrent apneas. Hypoxia-inducible factors (HIFs) 1 and 2 mediate transcriptional responses to low O(2). A previous study showed that HIF-1 mediates some of the IH-evoked physiological responses. Because HIF-2alpha is an orthologue of HIF-1alpha, we examined the effects of IH on HIF-2alpha, the O(2)-regulated subunit expression, in pheochromocytoma 12 cell cultures. In contrast to the up-regulation of HIF-1alpha, HIF-2alpha was down-regulated by IH. Similar down-regulation of HIF-2alpha 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-2alpha whereas inhibitors of prolyl hydroxylases or proteosome were ineffective. IH activated calpain proteases and down-regulated the endogenous calpain inhibitor calpastatin. IH-evoked HIF-2alpha degradation led to inhibition of SOD2 transcription, resulting in oxidative stress. Over-expression of transcriptionally active HIF-2alpha prevented IH-evoked oxidative stress and restored SOD2 activity. Systemic treatment of IH-exposed rats with ALLM rescued HIF-2alpha 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-2alpha via a calpain-dependent signaling pathway and results in oxidative stress as well as autonomic morbidities.
Nanduri
Jayasri
J
Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Wang
Ning
N
Yuan
Guoxiang
G
Khan
Shakil A
SA
Souvannakitti
Dangjai
D
Peng
Ying-Jie
YJ
Kumar
Ganesh K
GK
Garcia
Joseph A
JA
Prabhakar
Nanduri R
NR
D000818:Animals; D001049:Apnea / Q000201:enzymology* / Q000401:mortality; D001341:Autonomic Nervous System / Q000187:drug effects / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D002154:Calpain; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009842:Oligopeptides; D013482:Superoxide Dismutase; D000099162:Endothelial PAS Domain-Containing Protein 1; C069861:calpain inhibitor 2; C033668:calpastatin