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Inherent Variations in CO-H2S-Mediated Carotid Body O2 Sensing Mediate Hypertension and Pulmonary Edema

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Inherent Variations in CO-H2S-Mediated Carotid Body O2 Sensing Mediate Hypertension and Pulmonary Edema Inherent variations in CO-H2S-mediated carotid body O2 sensing mediate hypertension and pulmonary edema Ying-Jie Penga, Vladislav V. Makarenkoa, Jayasri Nanduria, Chirag Vasavdaa,b, Gayatri Raghuramana, Guoxiang Yuana, Moataz M. Gadallab,c, Ganesh K. Kumara, Solomon H. Snyderb,c,d,1, and Nanduri R. Prabhakara,1 a b Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, IL 60637; and The Solomon H. Snyder Department of Neuroscience, cDepartment of Pharmacology and Molecular Sciences, and dDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Contributed by Solomon H. Snyder, December 8, 2013 (sent for review October 29, 2013) Oxygen (O2) sensing by the carotid body and its chemosensory may reflect inherent variations in the O2 sensing ability of the reflex is critical for homeostatic regulation of breathing and blood carotid body. Although a number of hypotheses have been pro- pressure. Humans and animals exhibit substantial interindividual posed to explain carotid body-mediated O2 sensing (12, 13), variation in this chemosensory reflex response, with profound emerging evidence suggests that the gasotransmitter hydrogen effects on cardiorespiratory functions. However, the underlying sulfide (H2S) is required for O2 sensing by the carotid body (14– mechanisms are not known. Here, we report that inherent varia- 17). Hypoxia results in increased H2S generation in the carotid tions in carotid body O2 sensing by carbon monoxide (CO)-sensi- body. Glomus cells, the primary O2 sensing cells in the carotid tive hydrogen sulfide (H2S) signaling contribute to reflex variation body, express cystathionine-γ-lyase (CSE), an H2S catalyzing in three genetically distinct rat strains. Compared with Sprague- enzyme (15, 16). Homozygous CSE-null mice display diminished Dawley (SD) rats, Brown-Norway (BN) rats exhibit impaired carotid H2S generation and a severely impaired response to hypoxia (15, body O2 sensing and develop pulmonary edema as a consequence 16). We hypothesized that variations in the chemosensory reflex of poor ventilatory adaptation to hypobaric hypoxia. Spontaneous are a result of differences in H2S signaling in the carotid body. Hypertensive (SH) rat carotid bodies display inherent hypersensi- We tested this possibility by examining the carotid body response tivity to hypoxia and develop hypertension. BN rat carotid bodies to hypoxia in SD, BN, and SH rats and further assessed the have naturally higher CO and lower H2S levels than SD rat, physiological consequences of variations in carotid body O2 sensing whereas SH carotid bodies have reduced CO and greater H2S gen- on ventilatory adaptations to hypoxia and blood pressure. eration. Higher CO levels in BN rats were associated with higher substrate affinity of the enzyme heme oxygenase 2, whereas SH Results rats present lower substrate affinity and, thus, reduced CO gener- Variability in Carotid Body O2 Sensing. The carotid body hypoxic ation. Reducing CO levels in BN rat carotid bodies increased H2S response was assessed by measuring sensory activity from ex vivo generation, restoring O2 sensing and preventing hypoxia-induced preparations to exclude influences from circulating vasoactive pulmonary edema. Increasing CO levels in SH carotid bodies re- substances in intact rats. We examined the carotid body response duced H2S generation, preventing hypersensitivity to hypoxia to hypoxia in 5–6-wk-old SD, BN, and SH rats because SH rats and controlling hypertension in SH rats. develop hypertension beyond this age, potentially confounding results. The body weights of BN and SH rats were less than those high-altitude hypoxia | gasotransmitters | sympathetic tone | of SD rats (Table S1). BN carotid bodies exhibited lower baseline cystathionine-γ-lyase activity and a severely impaired response to hypoxia. In contrast, xygen, an essential substrate for generating ATP, is vital for Significance Osustaining much of life on earth. A low availability of oxy- gen directs vertebrates’ complex respiratory and cardiovascular The carotid body chemosensory reflex is a principal regulator systems to maintain optimal oxygenation of tissues by increasing of breathing and blood pressure. Humans and experimental ventilation and blood pressure. Interestingly, ventilatory responses animals display marked interindividual variation in the carotid to hypoxia are not uniform but, instead, exhibit substantial varia- body chemosensory reflex; however, the underlying mecha- tion among humans (1). These varied ventilatory responses to nisms are not known. Here, we demonstrate differences in hypoxia result in dire physiological consequences: a diminished carotid body O2 sensing to be mediated by inherent variations hypoxic ventilatory response can result in poor adaptation to low in carbon monoxide-sensitive hydrogen sulfide signaling in O2 environments (2) and high-altitude pulmonary edema (3–5), three distinct rat strains. Hyposensitivity of the carotid body to whereas a heightened response is associated with essential hy- hypoxia was associated with higher CO and lower H2S levels, pertension (6). Similar variations in hypoxic response have also poor ventilatory adaptation to hypobaric hypoxia, and pul- been documented in different strains of rodents (7–10). In monary edema. Hypersensitivity of the carotid body to low O2 comparison with Sprague-Dawley (SD) rats, Brown-Norway (BN) was accompanied by reduced CO, greater H2S generation, rats display a markedly reduced ventilatory response to hypoxia (8, and hypertension. 9), whereas Spontaneous Hypertensive (SH) rats exhibit an aug- mented response (11). SH rats also present enhanced sympathetic Author contributions: N.R.P. designed research; Y.-J.P., V.V.M., J.N., G.R., and G.Y. per- formed research; M.M.G. and S.H.S. contributed new reagents/analytic tools; Y.-J.P., nerve activity and hypertension (7). Despite the physiological V.V.M., J.N., C.V., G.R., and G.K.K. analyzed data; and C.V., G.K.K., S.H.S., and N.R.P. wrote significance, the mechanisms underlying interindividual variation the paper. in systemic responses to hypoxia are not known. The authors declare no conflict of interest. The carotid body is the key sensor of arterial blood oxygen, and 1To whom correspondence may be addressed. E-mail: [email protected] or nanduri@ its chemosensory reflex is a critical regulator of breathing, sym- uchicago.edu. pathetic tone, and blood pressure (12, 13). Differing responses in This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ventilation and sympathetic nerve activity to ambient oxygen levels 1073/pnas.1322172111/-/DCSupplemental. 1174–1179 | PNAS | January 21, 2014 | vol. 111 | no. 3 www.pnas.org/cgi/doi/10.1073/pnas.1322172111 Downloaded by guest on September 24, 2021 carotid bodies from SH rats showed elevated baseline activity and (19–21), blocked H2S generation in all three strains, suggesting an augmented hypoxic response (Fig. 1 A and B). that CSE is the primary H2S catalyzing enzyme in the carotid Sensory activity of BN carotid bodies treated with NaCN, a body (Fig. 2A). Immunocytochemistry of carotid body tissue potent carotid body stimulant, was comparable to SD, indicating showed no apparent differences in CSE-like immunoreactivity that the diminished BN hypoxic response was not a result of among the three strains (Fig. S3), suggesting that differential reduced excitability of sensory nerve endings (Fig. S1 A and B). CSE expression does not contribute to strain-dependent differ- Sensory response to CO2, another physiological stimulus, was ences in H2S generation. also comparable among all three strains (Fig. S1 C and D). To determine whether variations in the number of glomus Contribution of Carbon Monoxide to Altered H2S generation. Carbon cells, the primary O2 sensing cells, account for the differences in monoxide (CO) is a physiological inhibitor of CSE-generated carotid body O2 sensing, carotid body sections were stained for H2S in the carotid body (16). Carotid body CO measurements tyrosine hydroxylase, a marker of glomus cells (18) (Fig. 1C). revealed important differences across the three strains. Com- Morphometric analysis revealed no significant difference in the pared with SD, BN and SH carotid bodies exhibited higher and ratio of number of glomus cells to the total volume of carotid lower CO levels, respectively, under both normoxia and hypoxia body tissue among the three strains (Fig. 1D). (Fig. 2B). Heme oxygenase 2 (HO-2) is the primary CO-gener- Hypoxia induces catecholamine (CA) secretion from glomus ating enzyme in the carotid body (22). Treating BN rats with cells (15). Hypoxia-evoked CA secretion from individual cells Cr(III) meso porphyrin (CrMP), an HO inhibitor, markedly was monitored by carbon-fiber amperometry. Consistent with the decreased CO generation in the carotid body with a concomitant sensory nerve responses of the carotid body, the glomus cell increase in H2S generation in both normoxic and hypoxic con- hypoxic sensitivity was attenuated in BN and augmented in SH ditions (Fig. 2 C and D). The effects of HO inhibition on H2S relative to SD (Fig. 1 E and F). However, glomus cell CA se- generation were prevented by inhibiting CSE with L-PAG (Fig. 2 cretion was comparable across all three strains when treated with D). However, CSE inhibition had no effect on CO generation 40 mM KCl, a nonselective depolarizing stimulus (Fig. S1 E and (Fig. S4). Conversely, SH carotid bodies treated with CORM-2 F). These findings demonstrate inherent variation in O2 sensing ([Ru(CO)3 Cl2]2), a CO donor, decreased H2S generation in by the carotid body, where BN and SH rats are hypo- and hy- both normoxia and hypoxia (Fig. 2E). These data are consistent persensitive, respectively, to hypoxia relative to SD rats. with the notion that variations in CO levels determine differ- ences in H2S formation among the three rat strains. Altered H2S Generation in the Carotid Body. We then tested the We then examined whether correcting H2S generation nor- hypothesis that either altered H2S signaling and/or generation in malizes O2 sensing in BN and SH carotid bodies.
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