title: Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis.
abstract: Breathing and blood pressure are under constant homeostatic regulation to maintain optimal oxygen delivery to the tissues. Chemosensory reflexes initiated by the carotid body and catecholamine secretion from the adrenal medulla are the principal mechanisms for maintaining respiratory and cardiovascular homeostasis; however, the underlying molecular mechanisms are not known. Here, we report that balanced activity of hypoxia-inducible factor-1 (HIF-1) and HIF-2 is critical for oxygen sensing by the carotid body and adrenal medulla, and for their control of cardio-respiratory function. In Hif2α(+/-) mice, partial HIF-2α deficiency increased levels of HIF-1α and NADPH oxidase 2, leading to an oxidized intracellular redox state, exaggerated hypoxic sensitivity, and cardio-respiratory abnormalities, which were reversed by treatment with a HIF-1α inhibitor or a superoxide anion scavenger. Conversely, in Hif1α(+/-) mice, partial HIF-1α deficiency increased levels of HIF-2α and superoxide dismutase 2, leading to a reduced intracellular redox state, blunted oxygen sensing, and impaired carotid body and ventilatory responses to chronic hypoxia, which were corrected by treatment with a HIF-2α inhibitor. None of the abnormalities observed in Hif1α(+/-) mice or Hif2α(+/-) mice were observed in Hif1α(+/-);Hif2α(+/-) mice. These observations demonstrate that redox balance, which is determined by mutual antagonism between HIF-α isoforms, establishes the set point for hypoxic sensing by the carotid body and adrenal medulla, and is required for maintenance of cardio-respiratory homeostasis.
authors.affiliation: Biological Sciences Division, Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, University of Chicago, IL 60637, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Yuan
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Peng
authors.forename: Vaddi Damodara
authors.initials: VD
authors.lastname: Reddy
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Makarenko
authors.forename: Jayasri
authors.initials: J
authors.lastname: Nanduri
authors.forename: Shakil A
authors.initials: SA
authors.lastname: Khan
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Garcia
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Kumar
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Nanduri R
authors.initials: NR
authors.lastname: Prabhakar
mesh_terms: D000313:Adrenal Medulla / Q000502:physiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001794:Blood Pressure; D002319:Cardiovascular System; D002344:Carotid Body / Q000378:metabolism / Q000502:physiology*; D002395:Catecholamines / Q000378:metabolism; D006579:Heterozygote; D006706:Homeostasis; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099156:Superoxide Dismutase 2
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002395:Catecholamines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D010100:Oxygen; D013482:Superoxide Dismutase; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099156:Superoxide Dismutase 2; C488842:Cybb protein, mouse
keywords: Nox2; Sod2; blood pressure regulation; reactive oxygen species; ventilatory adaptation