The role of hypoxia‐inducible factors in carotid body (patho) physiology

Abstract

Hypoxia-inducible factors mediate adaptive responses to reduced O availability. In patients with obstructive sleep apnoea, repeated episodes of hypoxaemia and reoxygenation (intermittent hypoxia) are sensed by the carotid body (CB). The ensuing CB chemosensory reflex activates the sympathetic nervous system and increased secretion of catecholamines by the adrenal medulla, resulting in hypertension and breathing abnormalities. In the CB, intermittent hypoxia induces the formation of reactive oxygen species (ROS) and increased intracellular Ca levels, which drive increased expression of hypoxia-inducible factor (HIF) 1α and a decrease in the levels of HIF-2α. Intermittent hypoxia increases HIF-1α-dependent expression of Nox2, encoding the pro-oxidant enzyme NADPH oxidase 2, and decreased HIF-2α-dependent expression of Sod2, encoding the anti-oxidant enzyme superoxide dismutase 2. These changes in gene expression drive persistently elevated ROS levels in the CB, brainstem, and adrenal medulla that are required for the development of hypertension and breathing abnormalities. The ROS generated by dysregulated HIF activity in the CB results in oxidation and inhibition of haem oxygenase 2, and the resulting reduction in the levels of carbon monoxide leads to increased hydrogen sulfide production, triggering glomus cell depolarization. Thus, the pathophysiology of obstructive sleep apnoea involves the dysregulation of O -regulated transcription factors, gasotransmitters, and sympathetic outflow that affects blood pressure and breathing.

MECHANISMS OF ENDOCRINOLOGY: Mechanisms of disease: the endocrinology of obstructive sleep apnoea

“…In addition, several other neurohormonal mechanisms are involved in the links between OSA and T2D, which are summarised in Fig. 3 (30,39,51,65,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113).…”

“…On the other hand, dysglycaemia could lead to OSA. One plausible mechanism in patients with pre-diabetes or diabetes is autonomic neuropathy, which might impact on UA innervation (6), ventilatory drive and central respiratory responses to hypercapnia (109,110). In addition, T2D is associated with reduced pulmonary volumes and functions compared to healthy individuals which could affect UA stability (111,112,113,114,115,116,117,118,119,120,121) and diffusion capacity for carbon monoxide (112,113,122,123).…”

Oxygen therapy of the newborn from molecular understanding to clinical practice

“…Today it is known that more than 2500 target genes are activated by HIF. [54][55][56] Within any given cell, HIF activates promoters in the region of hypoxiaresponsive elements (HREs) and increases the expression of hundreds of messenger RNAs and decreases the expression of a similar number. These molecular mechanisms lead to either an increase in oxygen delivery or a decrease in oxygen consumption.…”

Advances in cellular and integrative control of oxygen and carbon dioxide homeostasis

“…Semenza and Prabhakar () extend this discussion of oxygen sensing in the carotid body to the effects of repeated or chronic intermittent bouts of hypoxia (CIH) on expression and function of hypoxia‐inducible factors (HIFs) in the carotid body. Cumulative studies indicate that altered HIFs lead to elevated reactive oxygen species in the carotid body that modulate oxygen sensing pathways, resulting in persistent activation of neural output from the carotid body.…”

“…The review by Rakoczy and Wyatt (2018) summarizes contemporary theories of oxygen sensing in the carotid body by discussing their possible interactions, links and incongruences at the microenvironment level within type I cells. Semenza and Prabhakar (2018) extend this discussion of oxygen sensing in the carotid body to the effects of repeated or chronic intermittent bouts of hypoxia (CIH) on expression and function of hypoxia-inducible factors (HIFs) in the carotid body. Cumulative studies indicate that altered HIFs lead to elevated reactive oxygen species in the carotid body that modulate oxygen sensing pathways, resulting in persistent activation of neural output from the carotid body.…”