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The role of hypoxia‐inducible factors in carotid body (patho) physiology
Author(s) -
Semenza Gregg L.,
Prabhakar Nanduri R.
Publication year - 2018
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp275696
Subject(s) - sod2 , carotid body , endocrinology , nox4 , glomus cell , medicine , hypoxia (environmental) , nadph oxidase , intermittent hypoxia , reactive oxygen species , oxidative stress , heme oxygenase , chemistry , superoxide dismutase , biology , obstructive sleep apnea , biochemistry , oxygen , enzyme , heme , stimulation , organic chemistry
Hypoxia‐inducible factors mediate adaptive responses to reduced O 2 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 2+ 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 2 ‐regulated transcription factors, gasotransmitters, and sympathetic outflow that affects blood pressure and breathing.