H ₂ S mediates O ₂ sensing in the carotid body

Abstract

Gaseous messengers, nitric oxide and carbon monoxide, have been implicated in O 2 sensing by the carotid body, a sensory organ that monitors arterial blood O 2 levels and stimulates breathing in response to hypoxia. We now show that hydrogen sulfide (H 2 S) is a physiologic gasotransmitter of the carotid body, enhancing its sensory response to hypoxia. Glomus cells, the site of O 2 sensing in the carotid body, express cystathionine γ-lyase (CSE), an H 2 Sgenerating enzyme, with hypoxia increasing H 2 S generation in a stimulus-dependent manner. Mice with genetic deletion of CSE display severely impaired carotid body response and ventilatory stimulation to hypoxia, as well as a loss of hypoxia-evoked H 2 S generation. Pharmacologic inhibition of CSE elicits a similar phenotype in mice and rats. Hypoxia-evoked H 2 S generation in the carotid body seems to require interaction of CSE with hemeoxygenase-2, which generates carbon monoxide. CSE is also expressed in neonatal adrenal medullary chromaffin cells of rats and mice whose hypoxia-evoked catecholamine secretion is greatly attenuated by CSE inhibitors and in CSE knockout mice.I n adult mammals, carotid bodies are the sensory organs responsible for monitoring arterial blood O 2 concentrations and relay sensory information to the brainstem neurons associated with regulation of breathing and the cardiovascular system (1). Carotid bodies are comprised mainly of two cell types: glomus (also called type I) and sustanticular (or type II) cells. Glomus cells, of neuronal nature, are considered the main hypoxiasensing cells. The gaseous messengers, carbon monoxide (CO) and nitric oxide (NO), generated by hemeoxygenase-2 (HO-2) and neuronal nitric oxide synthase (nNOS), respectively, physiologically inhibit carotid body activity (2-4). Because HO-2 and nNOS require molecular O 2 for their activity, stimulation of carotid body activity by hypoxia may reflect in part reduced formation of CO and NO (5).Like NO and CO, hydrogen sulfide (H 2 S) is a gasotransmitter physiologically regulating neuronal transmission (6) and vascular tone (7). Cystathionine γ-lyase (CSE) (EC 4.4.1.1) and cystathionine β-synthase (CBS) (4.2.1.22) are the major enzymes associated with generation of endogenous H 2 S (8, 9). CBS is the predominant H 2 S-synthesizing enzyme in the brain, CSE preponderates in the peripheral tissues whose H 2 S levels are reduced 90% in CSE −/− mice (7-10). Given that carotid bodies are peripheral organs and that H 2 S is redox active, we hypothesized that CSE-derived H 2 S plays a role in hypoxic sensing by the carotid body. We examined carotid body response to hypoxia in wild-type (CSE +/+ ) and CSE −/− mice as well as in rats treated with CSE inhibitor. Genetic deletion or pharmacologic inhibition of CSE dramatically impairs hypoxic sensing by the carotid body as well as in neonatal adrenal medullary chromaffin cells (AMC). ResultsLoss of Carotid Body Response to Hypoxia in CSE −/− Mice. CSE immunoreactivity was seen in glomus cells of carotid bodies from CSE +/+ mice...

Hydrogen sulfide (H2S) and hypoxia inhibit salmonid gastrointestinal motility: evidence for H2S as an oxygen sensor

“…P O2 , (4) inhibitors of H 2 S synthesis inhibit hypoxic responses, and (5) potential sulfide donors augment the hypoxic responses. Recent studies on the mammalian carotid body Peng et al, 2010;Telezhkin et al, 2009;Telezhkin et al, 2010) and kidney (Beltowski, 2010) have supported this hypothesis and our assertion that this is a phylogenetically ancient and ubiquitous O 2 -sensing mechanism. The present study extends these observations to the fish GI tract and supports the hypothesis that O 2 -dependent H 2 S metabolism is a fundamental oxygen-sensing mechanism.…”

“…the 'O 2 sensor' . Evidence for this mechanism has been found in systemic and respiratory vascular smooth muscle Olson et al, 2008a;, urinary bladder smooth muscle , chromaffin cells (Perry et al, 2009) and O 2 -sensing chemoreceptor cells Olson et al, 2008b;Peng et al, 2010;Telezhkin et al, 2009;Telezhkin et al, 2010).…”

Hydrogen sulfide as an oxygen sensor

“…5B), and an increase in afferent nerve activity is often observed when Po 2 falls below 100 mmHg (16,97,136). Glomus activation is often regarded as a sequential process by which the O 2 sensor (CO, H 2 S, inhibition of oxidative phosphorylation, i.e., the metabolic hypothesis, or others) initiates potassium channel closure and the resulting cellular depolarization increases calcium entry.…”

Gas biology: small molecular medicine

“…Remarkably, carotid bodies from mice that are heterozygous for a knockout allele at the locus encoding HIF-1α do not respond to hypoxia [15], whereas carotid bodies from mice that are heterozygous for a knockout allele at the locus encoding HIF-2α show exaggerated responses to hypoxia [16], providing evidence that the homeostatic responses mediated by the carotid body are dependent upon a balance between HIF-1 and HIF-2. Glomus cells express CSE and carotid bodies from mice lacking CSE also do not respond to hypoxia [17], whereas NOS1-deficient mice exhibit exaggerated ventilatory responses to hypoxia [18]. Treatment with a CO donor blocks hypoxia-induced H 2 S production, suggesting that CO produced by HO2 inhibits CSE activity in the carotid body [17], although the mechanism of action is unknown because, unlike CBS, CSE does not contain a heme group to which CO can bind.…”

“…Glomus cells express CSE and carotid bodies from mice lacking CSE also do not respond to hypoxia [17], whereas NOS1-deficient mice exhibit exaggerated ventilatory responses to hypoxia [18]. Treatment with a CO donor blocks hypoxia-induced H 2 S production, suggesting that CO produced by HO2 inhibits CSE activity in the carotid body [17], although the mechanism of action is unknown because, unlike CBS, CSE does not contain a heme group to which CO can bind. The targets of sulfhydration by H 2 S in the carotid body also remain to be determined.…”