Research ArticlePhysiology

H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea

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Science Signaling  16 Aug 2016:
Vol. 9, Issue 441, pp. ra80
DOI: 10.1126/scisignal.aaf3204

Sleeping with lower blood pressure

Individuals with sleep apnea periodically stop breathing or breathe more shallowly while sleeping. The resulting intermittent decreases in blood oxygen concentrations or hypoxia activates an organ called the carotid body, which sends out signals to increase breathing, but these signals also increase blood pressure and can lead to hypertension. Yuan et al. found that exposure of rodents to bouts of intermittent hypoxia similar to that seen in sleep apnea triggered the production of reactive oxygen species in the carotid body. These reactive oxygen species increased the generation of the gasotransmitter hydrogen sulfide, which stimulates carotid body activity. Inhibiting the enzyme that generates hydrogen sulfide prevented the development of high blood pressure in this rodent model of sleep apnea. Thus, inhibitors of the enzyme that produces hydrogen sulfide could be used to prevent the hypertension associated with sleep apnea.


Sleep apnea is a prevalent respiratory disease in which episodic cessation of breathing causes intermittent hypoxia. Patients with sleep apnea and rodents exposed to intermittent hypoxia exhibit hypertension. The carotid body senses changes in blood O2 concentrations, and an enhanced carotid body chemosensory reflex contributes to hypertension in sleep apnea patients. A rodent model of intermittent hypoxia that mimics blood O2 saturation profiles of patients with sleep apnea has shown that increased generation of reactive oxygen species (ROS) in the carotid body enhances the chemosensory reflex and triggers hypertension. CO generated by heme oxygenase-2 (HO-2) induces a signaling pathway that inhibits hydrogen sulfide (H2S) production by cystathionine γ-lyase (CSE), leading to suppression of carotid body activity. We found that ROS inhibited CO generation by HO-2 in the carotid body and liver through a mechanism that required Cys265 in the heme regulatory motif of heterologously expressed HO-2. We showed that ROS induced by intermittent hypoxia inhibited CO production and increased H2S concentrations in the carotid body, which stimulated its neural activity. In rodents, blockade of H2S synthesis by CSE, by either pharmacologic or genetic approaches, inhibited carotid body activation and hypertension induced by intermittent hypoxia. Thus, our results indicate that oxidant-induced inactivation of HO-2, which leads to increased CSE-dependent H2S production in the carotid body, is a critical trigger of hypertension in rodents exposed to intermittent hypoxia.

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