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Gaseous messengers in oxygen sensing

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Abstract

The carotid body is a sensory organ that detects acute changes in arterial blood oxygen (O2) levels and reflexly mediates systemic cardiac, vascular, and respiratory responses to hypoxia. This article provides a brief update of the roles of gas messengers as well as redox homeostasis by hypoxia-inducible factors (HIFs) in hypoxic sensing by the carotid body. Carbon monoxide (CO) and nitric oxide (NO), generated by heme oxygenase-2 (HO-2) and neuronal nitric oxide synthase (nNOS), respectively, inhibit carotid body activity. Molecular O2 is a required substrate for the enzymatic activities of HO-2 and nNOS. Stimulation of carotid body activity by hypoxia may reflect reduced formation of CO and NO. Glomus cells, the site of O2 sensing in the carotid body, express cystathionine γ-lyase (CSE), an H2S generating enzyme. Cth −/− mice, which lack CSE, exhibit severely impaired hypoxia-induced H2S generation, sensory excitation, and stimulation of breathing in response to low O2. Hypoxia-evoked H2S generation in the carotid body requires the interaction of CSE with HO-2, which generates CO. Carotid bodies from Hif1a +/− mice with partial HIF-1α deficiency do not respond to hypoxia, whereas carotid bodies from mice with partial HIF-2α deficiency are hyper-responsive to hypoxia. The opposing roles of HIF-1α and HIF-2α in the carotid body have provided novel insight into molecular mechanisms of redox homeostasis and its role in hypoxia sensing. Heightened carotid body activity has been implicated in the pathogenesis of autonomic morbidities associated with sleep-disordered breathing, congestive heart failure, and essential hypertension. The enzymes that generate gas messengers and redox regulation by HIFs represent potential therapeutic targets for normalizing carotid body function and downstream autonomic output in these disease states.

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Acknowledgments

This work was supported by the National Institutes of Health grants HL-76537, HL-90554, and HL-86493 (N.R.P) and the Johns Hopkins Institute for Cell Engineering (G.L.S).

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Authors and Affiliations

  1. Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, IL, 60637, USA

    Nanduri R. Prabhakar

  2. Vascular Program, Institute for Cell Engineering; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry; and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Gregg L. Semenza

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Correspondence to Nanduri R. Prabhakar.

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Prabhakar, N.R., Semenza, G.L. Gaseous messengers in oxygen sensing. J Mol Med 90, 265–272 (2012). https://doi.org/10.1007/s00109-012-0876-1

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