title: H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea.
abstract: 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 Cys(265) 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.
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Yuan
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Peng
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Shakil A
authors.initials: SA
authors.lastname: Khan
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jayasri
authors.initials: J
authors.lastname: Nanduri
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Amritha
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Chirag
authors.initials: C
authors.lastname: Vasavda
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Kumar
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA. nanduri@uchicago.edu.
authors.forename: Nanduri R
authors.initials: NR
authors.lastname: Prabhakar
mesh_terms: D000818:Animals; D002344:Carotid Body / Q000378:metabolism* / Q000503:physiopathology; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012891:Sleep Apnea Syndromes / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D017382:Reactive Oxygen Species; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide