Gasotransmitters in Sleep Apnea

Abstract

Sleep apnea is a highly prevalent respiratory disease, affecting an estimated 10% of adult human population. Sleep apneas are characterized by periodic cessations of breathing during sleep and are associated with several sequelae including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity is one of the major drivers of sleep apnea. Because gaseous molecules, carbon monoxide (CO) and hydrogen sulfide (H2S) are important determinants of CB activity we hypothesized that aberrations in their signaling could lead to sleep apnea. We tested this possibility in mice deficient in heme oxygenase‐2 (HO‐2), which catalyzes the endogenous production of CO. Basal breathing was monitored in unsedated 6‐to‐9 months old wild‐type and HO‐2−/− mice by plethysmography. A majority of the HO‐2−/− mice (40/70 mice, 57%) had 20 or more apnea events per hour. In contrast, only 2/40 wild‐type mice (5%) exhibited such frequent apneas. The apnea index was higher in 6–9 month old mice compared to 6–9 weeks old HO‐2−/− mice. Fifty‐six percent of the HO‐2−/− mice (39/70) had a hypopnea index of > 80 (breathing events with ≥ 30% reduction in tidal volume per hour), whereas only 2.5% of the wild‐type mice (1/40 mice) displayed a similar hypopnea index. Apneas and hyponeas were remarkably higher in non‐rapid eye movement (NREM) and REM sleep. Further characterization of apneas revelead that HO‐2−/− mice experience both obstructive and central apneas, and the incidence of former was greater than the latter. Hyperoxia, which inhibits the CB activity reduced, whereas hypoxia, which stimulates the CB activity increased the incidence of apneas. We identified hydrogen sulfide (H2S), as a major molecule driving apneas. Genetically ablating the H2S‐synthesizing enzyme cystathionine‐g‐lyase (CSE) or pharmacologic blockade of CSE normalized breathing in HO‐2−/− mice. These observations demonstrate that dysregulated CO and H2S signaling in the CB leads to apneas.Support or Funding InformationSupported by NIH‐UH3‐HL90554 and PO1‐HL90554