title: Enhanced leukocyte HIF-1alpha and HIF-1 DNA binding in humans after rapid ascent to 4300 m.
abstract: Hypoxia plays a crucial role in the pathogenesis of a multitude of diseases and clinical conditions such as cancer, diabetes, cardiovascular disease, stroke, pulmonary disease, inflammation, organ transplant, and wound healing. Investigations into the role of hypoxia-inducible transcription factor (HIF) in disease development have been conducted with the basic premise that HIF is activated in vivo during hypoxia in humans, yet this basic physiologic premise has never verified. Thus, we hypothesized that HIF-1 DNA binding would be enhanced in vivo in humans in response to acute global hypoxia. Fourteen human subjects were exposed to normoxia (1600 m) and hypoxia (4300 m, approximately 12% O(2)) in a hypobaric hypoxic chamber (8 h). HIF-1 DNA binding and HIF-1alpha protein were evaluated in circulating leukocytes. Oxidative markers were evaluated by plasma metabolomics using nuclear magnetic resonance and by urinary 15-F(2t)-isoprostane concentrations. Leukocyte HIF-1 DNA binding was increased (p=0.007) and HIF-1alpha was greater during hypoxia compared to normoxia. Circulating total glutathione was reduced by 35% (p=0.001), and lactate and succinate were increased by 29 and 158%, respectively (p=0.007 and 0.001), as were urinary 15-F(2t)-isoprostanes (p=0.037). HIF-1 DNA binding and HIF-1alpha were elevated in vivo in leukocytes of healthy human subjects exposed to 12% oxygen, in association with plasma and urinary markers of hypoxic stress.
authors.affiliation: Department of Anesthesiology, University of Colorado at Denver School of Medicine, Aurora, CO 80045, USA. martha.tissotvanpatot@uchsc.edu
authors.forename: Martha C
authors.initials: MC
authors.lastname: Tissot van Patot
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.forename: Robert C
authors.initials: RC
authors.lastname: Roach
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Henthorn
authors.forename: Benjamin
authors.initials: B
authors.lastname: Honigman
mesh_terms: D000328:Adult; D000531:Altitude; D015415:Biomarkers / Q000097:blood / Q000652:urine; D004247:DNA / Q000032:analysis*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000652:urine; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000097:blood; D006339:Heart Rate; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000473:pathology; D008297:Male; D055432:Metabolomics; D019906:Nuclear Magnetic Resonance, Biomolecular; D018384:Oxidative Stress; D011485:Protein Binding; D019802:Succinic Acid / Q000097:blood
chemical_list: D015415:Biomarkers; D005609:Free Radicals; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C075750:8-epi-prostaglandin F2alpha; D019344:Lactic Acid; D004247:DNA; D019802:Succinic Acid; D015237:Dinoprost; D005978:Glutathione