Regulation of carotid body oxygen sensing by hypoxia-inducible factors.
Oxygen (O2) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Carotid body responses to hypoxia are not uniform but instead exhibit remarkable inter-individual variations. The molecular mechanisms underlying variations in carotid body O2 sensing are not known. Hypoxia-inducible factor-1 (HIF-1) and HIF-2 mediate transcriptional responses to hypoxia. This article reviews the emerging evidence that proper expression of the HIF-α isoforms is a key molecular determinant for carotid body O2 sensing. HIF-1α deficiency leads to a blunted carotid body hypoxic response, which is due to increased abundance of HIF-2α, elevated anti-oxidant enzyme activity, and a reduced intracellular redox state. Conversely, HIF-2α deficiency results in augmented carotid body sensitivity to hypoxia, which is due to increased abundance of HIF-1α, elevated pro-oxidant enzyme activity, and an oxidized intracellular redox state. Double heterozygous mice with equally reduced HIF-1α and HIF-2α showed no abnormality in redox state or carotid body O2 sensing. Thus, mutual antagonism between HIF-α isoforms determines the redox state and thereby establishes the set point for hypoxic sensing by the carotid body.
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Sciences Division, The University of Chicago, Chicago, IL, 60637, USA. nanduri@uchicago.edu.
Nanduri R
NR
Prabhakar
Institute for Cell Engineering; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. gsemenza@jhmi.edu.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. gsemenza@jhmi.edu.
Gregg L
GL
Semenza
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002344:Carotid Body / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D000099162:Endothelial PAS Domain-Containing Protein 1
Hypertension; NADPH oxidase 2; Sleep apnea; Superoxide dismutase 2; Sympathetic nerve activity