PMID- 23610397
OWN - NLM
STAT- MEDLINE
DCOM- 20130719
LR  - 20220902
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 19
DP  - 2013 May 7
TI  - Mutual antagonism between hypoxia-inducible factors 1alpha and 2alpha regulates oxygen 
      sensing and cardio-respiratory homeostasis.
PG  - E1788-96
LID - 10.1073/pnas.1305961110 [doi]
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 
      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 Hif2alpha(+/-) mice, partial HIF-2alpha deficiency 
      increased levels of HIF-1alpha 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-1alpha 
      inhibitor or a superoxide anion scavenger. Conversely, in Hif1alpha(+/-) mice, 
      partial HIF-1alpha deficiency increased levels of HIF-2alpha 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-2alpha inhibitor. None of the abnormalities 
      observed in Hif1alpha(+/-) mice or Hif2alpha(+/-) mice were observed in 
      Hif1alpha(+/-);Hif2alpha(+/-) mice. These observations demonstrate that redox balance, 
      which is determined by mutual antagonism between HIF-alpha isoforms, establishes the 
      set point for hypoxic sensing by the carotid body and adrenal medulla, and is 
      required for maintenance of cardio-respiratory homeostasis.
FAU - Yuan, Guoxiang
AU  - Yuan G
AD  - Biological Sciences Division, Institute for Integrative Physiology and Center for 
      Systems Biology of O2 Sensing, University of Chicago, IL 60637, USA.
FAU - Peng, Ying-Jie
AU  - Peng YJ
FAU - Reddy, Vaddi Damodara
AU  - Reddy VD
FAU - Makarenko, Vladislav V
AU  - Makarenko VV
FAU - Nanduri, Jayasri
AU  - Nanduri J
FAU - Khan, Shakil A
AU  - Khan SA
FAU - Garcia, Joseph A
AU  - Garcia JA
FAU - Kumar, Ganesh K
AU  - Kumar GK
FAU - Semenza, Gregg L
AU  - Semenza GL
FAU - Prabhakar, Nanduri R
AU  - Prabhakar NR
LA  - eng
GR  - R01 HL076537/HL/NHLBI NIH HHS/United States
GR  - R01 HL086493/HL/NHLBI NIH HHS/United States
GR  - HL90554/HL/NHLBI NIH HHS/United States
GR  - HL86493/HL/NHLBI NIH HHS/United States
GR  - I01 BX000446/BX/BLRD VA/United States
GR  - HL76537/HL/NHLBI NIH HHS/United States
GR  - P01 HL090554/HL/NHLBI NIH HHS/United States
GR  - R01 HL108104/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Retracted Publication
DEP - 20130422
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Catecholamines)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Membrane Glycoproteins)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 1.15.1.1 (superoxide dismutase 2)
RN  - EC 1.6.3.- (Cybb protein, mouse)
RN  - EC 1.6.3.- (NADPH Oxidase 2)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - S88TT14065 (Oxygen)
SB  - IM
RIN - Proc Natl Acad Sci U S A. 2022 Sep 20;119(38):e2213287119. PMID: 36053740
MH  - Adrenal Medulla/physiology
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/*metabolism
MH  - Blood Pressure
MH  - Cardiovascular System
MH  - Carotid Body/metabolism/*physiology
MH  - Catecholamines/metabolism
MH  - Heterozygote
MH  - Homeostasis
MH  - Hypoxia
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Male
MH  - Membrane Glycoproteins/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - NADPH Oxidase 2
MH  - NADPH Oxidases/metabolism
MH  - Oxidation-Reduction
MH  - Oxygen/*metabolism
MH  - PC12 Cells
MH  - Rats
MH  - Superoxide Dismutase/metabolism
PMC - PMC3651442
OTO - NOTNLM
OT  - Nox2
OT  - Sod2
OT  - blood pressure regulation
OT  - reactive oxygen species
OT  - ventilatory adaptation
COIS- The authors declare no conflict of interest.
EDAT- 2013/04/24 06:00
MHDA- 2013/07/20 06:00
PMCR- 2013/10/22
CRDT- 2013/04/24 06:00
PHST- 2013/04/24 06:00 [entrez]
PHST- 2013/04/24 06:00 [pubmed]
PHST- 2013/07/20 06:00 [medline]
PHST- 2013/10/22 00:00 [pmc-release]
AID - 1305961110 [pii]
AID - 201305961 [pii]
AID - 10.1073/pnas.1305961110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 May 7;110(19):E1788-96. doi: 
      10.1073/pnas.1305961110. Epub 2013 Apr 22.