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

Abstract

Hypoxia-inducible factors mediate adaptive responses to reduced O₂ 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 Ca²⁺ 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 O₂ -regulated transcription factors, gasotransmitters, and sympathetic outflow that affects blood pressure and breathing.

Keywords: HIF-1; HIF-2; NADPH oxidase; Redox State; Superoxide dismutase; sleep apnea.

Figure 1. The chemosensory reflex pathway mediates rapid cardiovascular and respiratory responses to acute hypoxia

Abbreviations: ABP, arterial blood pressure; AM, adrenal medulla; ASN, adrenal sympathetic nerve; CB, carotid body; CSN, carotid sinus nerve, a branch of IX cranial nerve; HR, heart rate; nTS, nucleus tractus solitarius; RR, respiratory rate; RVLM, rostral ventrolateral medulla; SG, sympathetic ganglion.

Figure 2. O₂ sensing in carotid body glomus cells involves the generation of carbon monoxide and hydrogen sulfide gasotransmitters

Symbols: arrow, stimulation; blocked arrow, inhibition; curved arrow, substrate/product. Abbreviations: CO, carbon monoxide; CSE, cystathionine‐γ‐lyase; CSN, carotid sinus nerve; H₂S, hydrogen sulfide; HO2, haem oxygenase 2; PKG, protein kinase G; sGC, soluble guanylate cyclase.