RGD Reference Report - Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia. - Rat Genome Database

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Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia.

Authors: Yuan, G  Khan, SA  Luo, W  Nanduri, J  Semenza, GL  Prabhakar, NR 
Citation: Yuan G, etal., J Cell Physiol. 2011 Nov;226(11):2925-33. doi: 10.1002/jcp.22640.
RGD ID: 11040609
Pubmed: PMID:21302291   (View Abstract at PubMed)
PMCID: PMC4695992   (View Article at PubMed Central)
DOI: DOI:10.1002/jcp.22640   (Journal Full-text)

Sleep-disordered breathing with recurrent apnea is associated with intermittent hypoxia (IH). Cardiovascular morbidities caused by IH are triggered by increased generation of reactive oxygen species (ROS) by pro-oxidant enzymes, especially NADPH oxidase-2 (Nox2). Previous studies showed that (i) IH activates hypoxia-inducible factor 1 (HIF-1) in a ROS-dependent manner and (ii) HIF-1 is required for IH-induced ROS generation, indicating the existence of a feed-forward mechanism. In the present study, using multiple pharmacological and genetic approaches, we investigated whether IH-induced expression of Nox2 is mediated by HIF-1 in the central and peripheral nervous system of mice as well as in cultured cells. IH increased Nox2 mRNA, protein, and enzyme activity in PC12 pheochromocytoma cells as well as in wild-type mouse embryonic fibroblasts (MEFs). This effect was abolished or attenuated by blocking HIF-1 activity through RNA interference or pharmacologic inhibition (digoxin or YC-1) or by genetic knockout of HIF-1alpha in MEFs. Increasing HIF-1alpha expression by treating PC 12 cells with the iron chelator deferoxamine for 20 h or by transfecting them with HIF-1alpha expression vector increased Nox2 expression and enzyme activity. Exposure of wild-type mice to IH (8 h/day for 10 days) up-regulated Nox2 mRNA expression in brain cortex, brain stem, and carotid body but not in cerebellum. IH did not induce Nox2 expression in cortex, brainstem, carotid body, or cerebellum of Hif1a(+/-) mice, which do not manifest increased ROS or cardiovascular morbidities in response to IH. These results establish a pathogenic mechanism linking HIF-1, ROS generation, and cardiovascular pathology in response to IH.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to hypoxia  IEP 11040609 RGD 
hypoxia-inducible factor-1alpha signaling pathway  IMP 11040609 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cybb  (cytochrome b-245 beta chain)


Additional Information