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

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

Fingerprint

Carotid Body
Respiration
Hypertension
Oxidative Stress
Antioxidants
Electron Transport Complex I
Haploinsufficiency
Adrenal Medulla
Apnea
Oxidation-Reduction
Mammals
Norepinephrine
Homeostasis
Maintenance
Oxygen
Membranes
Enzymes
Hypoxia
endothelial PAS domain-containing protein 1

Keywords

  • Blood pressure
  • Catecholamines
  • Control of ventilation

ASJC Scopus subject areas

  • General

Cite this

Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. / Peng, Ying Jie; Nanduri, Jayasri; Khan, Shakil A.; Yuan, Guoxiang; Wang, Ning; Kinsman, Brian; Vaddi, Damodara R.; Kumar, Ganesh K.; Garcia, Joseph A.; Semenza, Gregg L; Prabhakar, Nanduri R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 7, 15.02.2011, p. 3065-3070.

Research output: Contribution to journalArticle

Peng, Ying Jie ; Nanduri, Jayasri ; Khan, Shakil A. ; Yuan, Guoxiang ; Wang, Ning ; Kinsman, Brian ; Vaddi, Damodara R. ; Kumar, Ganesh K. ; Garcia, Joseph A. ; Semenza, Gregg L ; Prabhakar, Nanduri R. / Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 7. pp. 3065-3070.
@article{de4e721b512843c2890bfa331659970f,
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 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.",
keywords = "Blood pressure, Catecholamines, Control of ventilation",
author = "Peng, {Ying Jie} and Jayasri Nanduri and Khan, {Shakil A.} and Guoxiang Yuan and Ning Wang and Brian Kinsman and Vaddi, {Damodara R.} and Kumar, {Ganesh K.} and Garcia, {Joseph A.} and Semenza, {Gregg L} and Prabhakar, {Nanduri R.}",
year = "2011",
month = "2",
day = "15",
doi = "10.1073/pnas.1100064108",
language = "English (US)",
volume = "108",
pages = "3065--3070",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "7",

}

TY - JOUR

T1 - Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension

AU - Peng, Ying Jie

AU - Nanduri, Jayasri

AU - Khan, Shakil A.

AU - Yuan, Guoxiang

AU - Wang, Ning

AU - Kinsman, Brian

AU - Vaddi, Damodara R.

AU - Kumar, Ganesh K.

AU - Garcia, Joseph A.

AU - Semenza, Gregg L

AU - Prabhakar, Nanduri R.

PY - 2011/2/15

Y1 - 2011/2/15

N2 - 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.

AB - 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.

KW - Blood pressure

KW - Catecholamines

KW - Control of ventilation

UR - http://www.scopus.com/inward/record.url?scp=79952609061&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952609061&partnerID=8YFLogxK

U2 - 10.1073/pnas.1100064108

DO - 10.1073/pnas.1100064108

M3 - Article

C2 - 21288809

AN - SCOPUS:79952609061

VL - 108

SP - 3065

EP - 3070

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 7

ER -