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Contrasting effects of intermittent and sustained hypoxia on HIF‐2α expression
Author(s) -
Nanduri Jayasri,
Wang Ning,
Yuan Guoxiang,
Khan Shakil
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.1038.7
Subject(s) - calpain , calpastatin , sod2 , hypoxia (environmental) , intermittent hypoxia , oxidative stress , chemistry , endogeny , microbiology and biotechnology , hypoxia inducible factors , endocrinology , medicine , biology , enzyme , biochemistry , gene , oxygen , superoxide dismutase , organic chemistry , obstructive sleep apnea
Intermittent hypoxia (IH) occurs in many pathological conditions including recurrent apneas. Hypoxia‐Inducible Factor‐1 and 2 (HIF‐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‐2α, the O2 regulated subunit, is an orthologue of HIF‐1α, we examined the effects of IH on HIF‐2α expression, in PC12 cells. In contrast to the up‐regulation of HIF‐1α, IH down regulated HIF‐2α in a stimulus‐dependent and reversible manner. Sustained hypoxia, up‐regulated both HIF‐1 and 2α. Neither prolyl hydroxylases / proteosome nor changes in HIF‐2α mRNA could account for the IH‐induced HIF‐2α degradation. Calcium chelator (BAPTA) and calpain protease inhibitors (ALLM, ALLN) prevented IH‐evoked degradation of HIF‐2α. IH activated calpains and down‐regulated the endogenous calpain inhibitor calpastatin. IH‐evoked HIF‐2α degradation led to decreased SOD2 enzyme activity due to transcriptional down‐regulation, resulting in oxidative stress. Over expression of transcriptionally active HIF‐2α prevented IH‐evoked oxidative stress and restored SOD2 activity. These observations demonstrate that, unlike continuous hypoxia, IH leads to down‐regulation of HIF‐2α via a novel signaling pathway involving calpains resulting in oxidative stress. Supported by NIH‐HL‐90554 and HL‐76537.