title: Complementary roles of gasotransmitters CO and H2S in sleep apnea.
abstract: Sleep apnea, which is the periodic cessation of breathing during sleep, is a major health problem affecting over 10 million people in the United States and is associated with several sequelae, including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity may be a driver of sleep apnea. Because gaseous molecules are important determinants of CB activity, aberrations in their signaling could lead to sleep apnea. Here, we report that mice deficient in heme oxygenase-2 (HO-2), which generates the gaseous molecule carbon monoxide (CO), exhibit sleep apnea characterized by high apnea and hypopnea indices during rapid eye movement (REM) sleep. Similar high apnea and hypopnea indices were also noted in prehypertensive spontaneously hypertensive (SH) rats, which are known to exhibit CB hyperactivity. We identified the gaseous molecule hydrogen sulfide (H2S) as the major effector molecule driving apneas. Genetic ablation of the H2S-synthesizing enzyme cystathionine-γ-lyase (CSE) normalized breathing in HO-2-/-mice. Pharmacologic inhibition of CSE with l-propargyl glycine prevented apneas in both HO-2-/-mice and SH rats. These observations demonstrate that dysregulated CO and H2S signaling in the CB leads to apneas and suggest that CSE inhibition may be a useful therapeutic intervention for preventing CB-driven sleep apnea.
authors.affiliation: Institute of Integrative Physiology, Biological Sciences Division, University of Chicago, Chicago, IL 60637.|Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Peng
authors.affiliation: Institute of Integrative Physiology, Biological Sciences Division, University of Chicago, Chicago, IL 60637.|Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Integrative Physiology, Biological Sciences Division, University of Chicago, Chicago, IL 60637.|Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637.
authors.forename: Anna
authors.initials: A
authors.lastname: Gridina
authors.affiliation: Institute of Integrative Physiology, Biological Sciences Division, University of Chicago, Chicago, IL 60637.|Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637.
authors.forename: Irina
authors.initials: I
authors.lastname: Chupikova
authors.affiliation: Life Sciences Group, Illinois Institute of Technology Research Institute, Chicago, IL 60616.
authors.forename: David L
authors.initials: DL
authors.lastname: McCormick
authors.affiliation: Division of Pulmonary, Critical Care & Sleep, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Thomas
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Scammell
authors.affiliation: Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL 60637.
authors.forename: Gene
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Chirag
authors.identifier: 0000-0003-4558-4698
authors.initials: C
authors.lastname: Vasavda
authors.affiliation: Institute of Integrative Physiology, Biological Sciences Division, University of Chicago, Chicago, IL 60637.|Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637.
authors.forename: Jayasri
authors.initials: J
authors.lastname: Nanduri
authors.affiliation: Institute of Integrative Physiology, Biological Sciences Division, University of Chicago, Chicago, IL 60637.|Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637.
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Kumar
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; nanduri@uchicago.edu ssnyder@jhmi.edu.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.affiliation: Institute of Integrative Physiology, Biological Sciences Division, University of Chicago, Chicago, IL 60637; nanduri@uchicago.edu ssnyder@jhmi.edu.|Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, IL 60637.
authors.forename: Nanduri R
authors.initials: NR
authors.lastname: Prabhakar
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D002344:Carotid Body / Q000378:metabolism / Q000503:physiopathology; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D005260:Female; D064426:Gasotransmitters / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012119:Respiration / Q000235:genetics; D012891:Sleep Apnea Syndromes / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D064426:Gasotransmitters; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: central apnea; chemoreflex; hypertension; obstructive apnea; oxygen sensing