| First Author | Yuan G | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 19 | Pages | E1788-96 |
| PubMed ID | 23610397 | Mgi Jnum | J:197349 |
| Mgi Id | MGI:5492205 | Doi | 10.1073/pnas.1305961110 |
| Citation | Yuan G, et al. (2013) Mutual antagonism between hypoxia-inducible factors 1alpha and 2alpha regulates oxygen sensing and cardio-respiratory homeostasis. Proc Natl Acad Sci U S A 110(19):E1788-96 |
| abstractText | 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. |
