Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension

Ying Jie Peng, Jayasri Nanduri, Shakil A. Khan, Guoxiang Yuan, Ning Wang, Brian Kinsman, Damodara R. Vaddi, Ganesh K. Kumar, Joseph A. Garcia, Gregg L. Semenza, Nanduri R. Prabhakar

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Cardiorespiratory functions in mammals are exquisitely sensitive to changes in arterial O2 levels. Hypoxia-inducible factors (e.g., HIF-1 and HIF-2) mediate transcriptional responses to reduced oxygen availability. We demonstrate that haploinsufficiency for the O2-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.

Original languageEnglish (US)
Pages (from-to)3065-3070
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number7
DOIs
StatePublished - Feb 15 2011

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Keywords

  • Blood pressure
  • Catecholamines
  • Control of ventilation

ASJC Scopus subject areas

  • General

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