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 apnea, repeated episodes of hypoxemia 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 1α (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 heme oxygenase 2, and the resulting reduction in the levels of carbon monoxide lead to increased hydrogen sulfide production, triggering glomus cell depolarization. Thus, the pathophysiology of obstructive sleep apnea involves the dysregulation of O₂-regulated transcription factors, gasotransmitters, and sympathetic outflow that affects blood pressure and breathing.

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