Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis

Guoxiang Yuan, Ying Jie Peng, Vaddi Damodara Reddy, Vladislav V. Makarenko, Jayasri Nanduri, Shakil A. Khan, Joseph A. Garcia, Ganesh K. Kumar, Gregg L Semenza, Nanduri R. Prabhakar

Research output: Contribution to journalArticle

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 principalmechanisms 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 adrenalmedulla, 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 bymutual 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 cardiorespiratory homeostasis.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number19
DOIs
StatePublished - May 7 2013

Fingerprint

Hypoxia-Inducible Factor 1
Carotid Body
Homeostasis
Oxygen
Oxidation-Reduction
Adrenal Medulla
NADPH Oxidase
Superoxides
Catecholamines
Reflex
Protein Isoforms
Respiration
Maintenance
endothelial PAS domain-containing protein 1
Blood Pressure
Therapeutics

Keywords

  • Blood pressure regulation
  • Nox2
  • Reactive oxygen species
  • Sod2
  • Ventilatory adaptation

ASJC Scopus subject areas

  • General

Cite this

Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis. / Yuan, Guoxiang; Peng, Ying Jie; Reddy, Vaddi Damodara; Makarenko, Vladislav V.; Nanduri, Jayasri; Khan, Shakil A.; Garcia, Joseph A.; Kumar, Ganesh K.; Semenza, Gregg L; Prabhakar, Nanduri R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 19, 07.05.2013.

Research output: Contribution to journalArticle

Yuan, Guoxiang ; Peng, Ying Jie ; Reddy, Vaddi Damodara ; Makarenko, Vladislav V. ; Nanduri, Jayasri ; Khan, Shakil A. ; Garcia, Joseph A. ; Kumar, Ganesh K. ; Semenza, Gregg L ; Prabhakar, Nanduri R. / Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 19.
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AU - Peng, Ying Jie

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AU - Makarenko, Vladislav V.

AU - Nanduri, Jayasri

AU - Khan, Shakil A.

AU - Garcia, Joseph A.

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AU - Prabhakar, Nanduri R.

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AB - 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 principalmechanisms 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 adrenalmedulla, 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 bymutual 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 cardiorespiratory homeostasis.

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