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

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 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 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 Hif1αmice. These observations demonstrate that redox balance, which is determined by mutual 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.blood pressure regulation | ventilatory adaptation | reactive oxygen species | Nox2 | Sod2

Alterations in Carotid Body Morphology and Cellular Mechanism Under the Influence of Intermittent Hypoxia

“…Previous workers have shown that HIF1α is found ubiquitously in vivo whereas HIF2α is tissue specific and is upregulated in specific cells of different organs [25,7]. However, both the isoforms of HIFα are expressed within the CB and are already considered as the master regulators of O 2 homeostasis.…”

“…However, both the isoforms of HIFα are expressed within the CB and are already considered as the master regulators of O 2 homeostasis. Chronic hypoxia activates both HIF1α and HIF2α [26] and has various maladaptive effects on CB structure and function [10,6,7]. Several clinical manifestations of sustained hypoxia can be seen in patients of chronic mountain sickness, chronic obstructive pulmonary disease (COPD), cerebral ischemia, pulmonary arterial hypertension, etc in which HIFs play a vital role [27,26].…”

“…HIF1α and HIF2α mediate expression of different gene products with opposing functions in the CB [7]. Changes in the HIF1α levels are associated with changes in the expression of Nox2 gene encoding NOX2 [7] that acts as a pro-oxidant enzyme associated with a sharp increase of O 2 uptake and catalyze the production of ROS (superoxide or O 2 .-) which subsequently activate different cellular responses.…”

“…HIF1α and HIF2α mediate expression of different gene products with opposing functions in the CB [7]. Changes in the HIF1α levels are associated with changes in the expression of Nox2 gene encoding NOX2 [7] that acts as a pro-oxidant enzyme associated with a sharp increase of O 2 uptake and catalyze the production of ROS (superoxide or O 2 .-) which subsequently activate different cellular responses. We verified the NOX2 expression immunohistochemically in the rat CBs of different groups which was earlier histochemically observed to be present in the type I cells and macrophages within the CB [28].…”

“…Other than these, HIF1 and HIF2, members of hypoxia inducible factor (HIF) family are believed to be chief molecular determinants for CB O 2 sensing. They constitute a common HIFβ subunit with oxygen regulated HIF1α and HIF2α subunits respectively [6,7]. HIF1α is a potent activator of genes encoding pro-oxidant enzymes such as NADPH oxidase 2 (NOX2) [8] and HIF2α regulates antioxidant enzymes such as superoxide dismutase 2 (SOD2) [9].…”