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Complementary roles of gasotransmitters CO and H2S in sleep apnea.
Proc Natl Acad Sci U S A. 2017 02 07; 114(6):1413-1418.PN

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.

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Authors+Show Affiliations

Peng YJ
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.
Zhang X
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.
Gridina A
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.
Chupikova I
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.
McCormick DL
Life Sciences Group, Illinois Institute of Technology Research Institute, Chicago, IL 60616.
Thomas RJ
Division of Pulmonary, Critical Care & Sleep, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215.
Scammell TE
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215.
Kim G
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL 60637.
Vasavda C
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Nanduri J
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.
Kumar GK
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.
Semenza GL
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.
Snyder SH
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.
Prabhakar NR
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.

MeSH

AnimalsCarbon MonoxideCarotid BodyCystathionine gamma-LyaseFemaleGasotransmittersHeme Oxygenase (Decyclizing)Hydrogen SulfideMaleMice, Inbred C57BLMice, KnockoutRats, Inbred SHRRats, Inbred WKYRespirationSleep Apnea Syndromes

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28115703

Citation

Peng, Ying-Jie, et al. "Complementary Roles of Gasotransmitters CO and H2S in Sleep Apnea." Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 6, 2017, pp. 1413-1418.
Peng YJ, Zhang X, Gridina A, et al. Complementary roles of gasotransmitters CO and H2S in sleep apnea. Proc Natl Acad Sci U S A. 2017;114(6):1413-1418.
Peng, Y. J., Zhang, X., Gridina, A., Chupikova, I., McCormick, D. L., Thomas, R. J., Scammell, T. E., Kim, G., Vasavda, C., Nanduri, J., Kumar, G. K., Semenza, G. L., Snyder, S. H., & Prabhakar, N. R. (2017). Complementary roles of gasotransmitters CO and H2S in sleep apnea. Proceedings of the National Academy of Sciences of the United States of America, 114(6), 1413-1418. https://doi.org/10.1073/pnas.1620717114
Peng YJ, et al. Complementary Roles of Gasotransmitters CO and H2S in Sleep Apnea. Proc Natl Acad Sci U S A. 2017 02 7;114(6):1413-1418. PubMed PMID: 28115703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Complementary roles of gasotransmitters CO and H2S in sleep apnea. AU - Peng,Ying-Jie, AU - Zhang,Xiuli, AU - Gridina,Anna, AU - Chupikova,Irina, AU - McCormick,David L, AU - Thomas,Robert J, AU - Scammell,Thomas E, AU - Kim,Gene, AU - Vasavda,Chirag, AU - Nanduri,Jayasri, AU - Kumar,Ganesh K, AU - Semenza,Gregg L, AU - Snyder,Solomon H, AU - Prabhakar,Nanduri R, Y1 - 2017/01/23/ PY - 2017/1/25/pubmed PY - 2018/4/17/medline PY - 2017/1/25/entrez KW - central apnea KW - chemoreflex KW - hypertension KW - obstructive apnea KW - oxygen sensing SP - 1413 EP - 1418 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 114 IS - 6 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/28115703/Complementary_roles_of_gasotransmitters_CO_and_H2S_in_sleep_apnea_ DB - PRIME DP - Unbound Medicine ER -