title: Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension.
abstract: Cardiorespiratory functions in mammals are exquisitely sensitive to changes in arterial O(2) levels. Hypoxia-inducible factors (e.g., HIF-1 and HIF-2) mediate transcriptional responses to reduced oxygen availability. We demonstrate that haploinsufficiency for the O(2)-regulated HIF-2α subunit results in augmented carotid body sensitivity to hypoxia, irregular breathing, apneas, hypertension, and elevated plasma norepinephrine levels in adult Hif-2α(+/-) mice. These dysregulated autonomic responses were associated with increased oxidative stress and decreased mitochondrial electron transport chain complex I activity in adrenal medullae as a result of decreased expression of major cytosolic and mitochondrial antioxidant enzymes. Systemic administration of a membrane-permeable antioxidant prevented oxidative stress, normalized hypoxic sensitivity of the carotid body, and restored autonomic functions in Hif-2α(+/-) mice. Thus, HIF-2α-dependent redox regulation is required for maintenance of carotid body function and cardiorespiratory homeostasis.
authors.affiliation: Biological Sciences Division, Institute for Integrated Physiology and Center for Systems Biology of O2 Sensing, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Peng
authors.forename: Jayasri
authors.initials: J
authors.lastname: Nanduri
authors.forename: Shakil A
authors.initials: SA
authors.lastname: Khan
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Yuan
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Brian
authors.initials: B
authors.lastname: Kinsman
authors.forename: Damodara R
authors.initials: DR
authors.lastname: Vaddi
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Kumar
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Garcia
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 / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure; D015153:Blotting, Western; D002344:Carotid Body / Q000502:physiology*; D042967:Electron Transport Complex I / Q000378:metabolism; D020869:Gene Expression Profiling; D006973:Hypertension / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010101:Oxygen Consumption; D010993:Plethysmography, Whole Body; D015656:Respiratory Mechanics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D042967:Electron Transport Complex I; D009638:Norepinephrine; D000099162:Endothelial PAS Domain-Containing Protein 1