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H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea.
Sci Signal. 2016 08 16; 9(441):ra80.SS

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+Show Affiliations

Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.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.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.Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.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.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.

Pub Type(s)

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

Language

eng

PubMed ID

27531649

Citation

Yuan, Guoxiang, et al. "H2S Production By Reactive Oxygen Species in the Carotid Body Triggers Hypertension in a Rodent Model of Sleep Apnea." Science Signaling, vol. 9, no. 441, 2016, pp. ra80.
Yuan G, Peng YJ, Khan SA, et al. H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea. Sci Signal. 2016;9(441):ra80.
Yuan, G., Peng, Y. J., Khan, S. A., Nanduri, J., Singh, A., Vasavda, C., Semenza, G. L., Kumar, G. K., Snyder, S. H., & Prabhakar, N. R. (2016). H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea. Science Signaling, 9(441), ra80. https://doi.org/10.1126/scisignal.aaf3204
Yuan G, et al. H2S Production By Reactive Oxygen Species in the Carotid Body Triggers Hypertension in a Rodent Model of Sleep Apnea. Sci Signal. 2016 08 16;9(441):ra80. PubMed PMID: 27531649.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea. AU - Yuan,Guoxiang, AU - Peng,Ying-Jie, AU - Khan,Shakil A, AU - Nanduri,Jayasri, AU - Singh,Amritha, AU - Vasavda,Chirag, AU - Semenza,Gregg L, AU - Kumar,Ganesh K, AU - Snyder,Solomon H, AU - Prabhakar,Nanduri R, Y1 - 2016/08/16/ PY - 2016/8/18/entrez PY - 2016/8/18/pubmed PY - 2017/11/29/medline SP - ra80 EP - ra80 JF - Science signaling JO - Sci Signal VL - 9 IS - 441 N2 - 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. SN - 1937-9145 UR - https://www.unboundmedicine.com/medline/citation/27531649/H2S_production_by_reactive_oxygen_species_in_the_carotid_body_triggers_hypertension_in_a_rodent_model_of_sleep_apnea_ L2 - https://stke.sciencemag.org/cgi/pmidlookup?view=long&pmid=27531649 DB - PRIME DP - Unbound Medicine ER -