Sensing hypoxia: physiology, genetics and epigenetics

  The carotid body is a sensory organ for detecting arterial blood O 2 levels and reflexly mediates systemic cardiac, vascular and respiratory responses to hypoxia. This article presents a brief review of the roles of gaseous messengers in the sensory transduction at the carotid body, genetic and epigenetic influences on hypoxic sensing and the role of the carotid body chemoreflex in cardiorespiratory diseases. Type I (also called glomus) cells, the site of O 2 sensing in the carotid body, express haem oxygenase‐2 and cystathionine‐γ‐lyase, the enzymes which catalyse the generation of CO and H 2 S, respectively. Physiological studies have shown that CO is an inhibitory gas messenger, which contributes to the low sensory activity during normoxia, whereas H 2 S is excitatory and mediates sensory stimulation by hypoxia. Hypoxia‐evoked H 2 S generation in the carotid body requires the interaction of cystathionine‐γ‐lyase with haem oxygenase‐2, which generates CO. Hypoxia‐inducible factors 1 and 2 constitute important components of the genetic make‐up in the carotid body, which influence hypoxic sensing by regulating the intracellular redox state via transcriptional regulation of pro‐ and antioxidant enzymes. Recent studies suggest that developmental programming of the carotid body response to hypoxia involves epigenetic changes, e.g. DNA methylation of genes encoding redox‐regulating enzymes. Emerging evidence implicates heightened carotid body chemoreflex in the progression of autonomic morbidities associated with cardiorespiratory diseases, such as sleep‐disordered breathing with apnoea, congestive heart failure and essential hypertension.