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 (HS) as the major effector molecule driving apneas. Genetic ablation of the HS-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 HS signaling in the CB leads to apneas and suggest that CSE inhibition may be a useful therapeutic intervention for preventing CB-driven sleep apnea.
The current study demonstrates that olfactory receptor 78 (Olfr78), a G protein-coupled receptor, is an integral component of the hypoxic sensing mechanism of the carotid body to a wide range of low oxygen levels, but not severe hypoxia, and that Olfr78 participation does not require either lactate or any other short-chain fatty acids, proposed ligands of Olfr78.
The role of cystathionine-γ-lyase (CSE) derived HS in the hypoxic and anoxic responses of the carotid body (CB) were examined. Experiments were performed on Sprague-Dawley rats, wild type and CSE knockout mice on C57BL/6 J background. Hypoxia (pO = 37 ± 3 mmHg) increased the CB sensory nerve activity and elevated HS levels in rats. In contrast, anoxia (pO = 5 ± 4 mmHg) produced only a modest CB sensory excitation with no change in HS levels. DL-propargylglycine (DL-PAG), a blocker of CSE, inhibited hypoxia but not anoxia-evoked CB sensory excitation and [Ca] elevation of glomus cells. The inhibitory effects of DL-PAG on hypoxia were seen: a) when it is dissolved in saline but not in dimethyl sulfoxide (DMSO), and b) in glomus cells cultured for18 h but not in cells either soon after isolation or after prolonged culturing (72 h) requiring 1-3 h of incubation. On the other hand, anoxia-induced [Ca] responses of glomus cell were blocked by high concentration of DL-PAG (300μM) either alone or in combination with aminooxyacetic acid (AOAA; 300μM) with a decreased cell viability. Anoxia produced a weak CB sensory excitation and robust [Ca] elevation in glomus cells of both wild-type and CSE null mice. As compared to wild-type, CSE null mice exhibited impaired CB chemo reflex as evidenced by attenuated efferent phrenic nerve responses to brief hyperoxia (Dejours test), and hypoxia. Inhalation of 100% N (anoxia) depressed breathing in both CSE null and wild-type mice. These observations demonstrate that a) hypoxia and anoxia are not analogous stimuli for studying CB physiology and b) CSE-derived HS contributes to CB response to hypoxia but not to that of anoxia.
Emerging evidence suggests that gaseous molecules, carbon monoxide (CO) and hydrogen sulfide (H2S) generated by heme oxygenase-(HO)-2 and cystathionine γ-lyase (CSE), respectively, function as transmitters in the nervous system. Present study examined the roles of CO and H2S in hypoxia-induced catecholamine (CA) release from adrenal medullary chromaffin cells (AMC). Studies were performed on AMC from adult (≥6 weeks of age) wild type (WT), HO-2 null, CSE null and HO-2/CSE double null mice of either gender. CA secretion was determined by carbon fiber amperometry and [Ca2+]i by microflurometry using Fura-2. HO-2- and CSE immunoreactivities were seen in WT AMC, which were absent in HO-2 and CSE null mice. Hypoxia (medium pO2 30-38 mmHg) evoked CA release and elevated [Ca2+]i. The magnitude of hypoxic response was greater in HO-2 null mice and in HO inhibitor treated WT AMC compared to controls. H2S levels were elevated in HO-2 null AMC. Either pharmacological inhibition or genetic deletion of CSE prevented the augmented hypoxic responses of HO-2 null AMC and H2S donor rescued AMC responses to hypoxia in HO-2/CSE double null mice. CORM-3, a CO donor, prevented the augmented hypoxic responses in WT and HO-2 null AMC. CO donor reduced H2S levels in WT AMC. The effects of CO donor were blocked by either ODQ or 8pCT, inhibitors of soluble guanylyl cyclase (SGC) or protein kinase G, respectively. These results suggest that HO-2-derived CO inhibits hypoxia-evoked CA secretion from adult murine AMC involving soluble guanylyl cyclase (SGC)-protein kinase G (PKG)-dependent regulation of CSE- derived H2S.
Carotid bodies are the sensory organs for detecting hypoxemia (decreased arterial blood oxygen levels) and ensuing chemo reflex is a major regulator of breathing and blood pressure. Chang et al (2015) proposed that olfactory receptor 78 (Olfr78) plays a major role in hypoxic sensing by the carotid body. However, such a possibility was questioned by a subsequent study ((Torres-Torrelo et al. 2018). The discrepancy between the two reports prompted the present study to reexamine the role of Olfr78 in hypoxic sensing by the carotid body (CB). Studies were performed on age and gender matched Olfr78 knock out mice generated on BL6 and JAX backgrounds and corresponding wild type mice. Breathing was monitored by plethysmography in un-sedated and efferent phrenic nerve activity in anesthetized mice. Carotid body sensory nerve activity was determined ex vivo and [Ca 2+ ]i responses were monitored in isolated glomus cells, the primary O2 sensing cells of the carotid body. Olfr78 null mice on both BL6 and JAX backgrounds exhibited attenuated hypoxic ventilatory response, whereas breathing responses to CO2 were unaffected.The magnitude of hyperoxia-induced depression of breathing (Dejour's test), which is an indirect measure of carotid body hypoxic sensing, was markedly reduced in Olfr78 mutant mice on both background strains. Furthermore, carotid body sensory nerve and glomus cell [Ca 2+ ]i responses to hypoxia were attenuated in BL6 and JAX Olfr78 null mice. These results suggest that Olfr78 plays an important role in hypoxic sensing by the carotid body.Key Words: G-protein coupled receptors, oxygen sensing, sensory nerve activity, hypoxic ventilator response, carotid body chemo reflex. METHODS Preparation of AnimalsExperimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Chicago. Experiments were performed on age-matched adult wild-type (WT) and Olfr78 null mice on C57BL/6 background (BL6, gift from Dr. J. Pluznick, Johns Hopkins University) and on 129P2/OlaHsd background (JAX, gift from Dr. A. Chang, The University of California, San Francisco, UCSF). Measurements of breathingWhole body plethysmography-Ventilation was monitored by whole-body plethysmograph (Buxco, DSI, St. Paul, MN), and O2 consumption and CO2 production were determined by the open-circuit method in un-sedated mice as described (Peng et al. 2006). Ventilation was recorded while the mice breathed 21% or 12% O2-balanced N2. Each gas challenge was given for 5 min.O2 consumption and CO2 production were measured at the end of each 5-min challenge. For determining ventilatory response to CO2, baseline ventilation was determined while mice breathed 100% O2 followed by hypercapnic challenge with 5% CO2-95% O2-balance N2. Sighs, sniffs, and movement-induced changes in breathing were monitored and excluded in the analysis.All recordings were made at an ambient temperature of 25 ± 1 °C. Minute ventilation (VE = Tidal volume, VT x respiratory rate, RR) was calculated and normalized for body weight and expressed as r...
According to the anamnesis data 38% of multiple sclerosis patient population had neuritis retrobulbaris as the first clinical symptom. The examination of visual evoked potentials detected that 88% of patients who had suffered from neuritis retrobulbaris earlier, and 19% of those, who had not, had changes revealing possible subclinical demyelinization of a visual nerve.
The Relapsing-Remitting Multiple Sclerosis (MS) patients research has revealed that the matrix metalloproteinase-2 level in cerebrospinal fluid which is higher then 30 ng/ml during the relapse and/or remission period increases repeated relapse risk during 2 years term by 2.8 times. The rapid MS progressing is associated with the high level of adhesion molecule (sPECAM) in cerebrospinal fluid.
Sleep apnea is a highly prevalent respiratory disease, affecting an estimated 10% of adult human population. Sleep apneas are characterized by periodic cessations of breathing during sleep and are associated with several sequelae including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity is one of the major drivers of sleep apnea. Because gaseous molecules, carbon monoxide (CO) and hydrogen sulfide (H2S) are important determinants of CB activity we hypothesized that aberrations in their signaling could lead to sleep apnea. We tested this possibility in mice deficient in heme oxygenase‐2 (HO‐2), which catalyzes the endogenous production of CO. Basal breathing was monitored in unsedated 6‐to‐9 months old wild‐type and HO‐2−/− mice by plethysmography. A majority of the HO‐2−/− mice (40/70 mice, 57%) had 20 or more apnea events per hour. In contrast, only 2/40 wild‐type mice (5%) exhibited such frequent apneas. The apnea index was higher in 6–9 month old mice compared to 6–9 weeks old HO‐2−/− mice. Fifty‐six percent of the HO‐2−/− mice (39/70) had a hypopnea index of > 80 (breathing events with ≥ 30% reduction in tidal volume per hour), whereas only 2.5% of the wild‐type mice (1/40 mice) displayed a similar hypopnea index. Apneas and hyponeas were remarkably higher in non‐rapid eye movement (NREM) and REM sleep. Further characterization of apneas revelead that HO‐2−/− mice experience both obstructive and central apneas, and the incidence of former was greater than the latter. Hyperoxia, which inhibits the CB activity reduced, whereas hypoxia, which stimulates the CB activity increased the incidence of apneas. We identified hydrogen sulfide (H2S), as a major molecule driving apneas. Genetically ablating the H2S‐synthesizing enzyme cystathionine‐g‐lyase (CSE) or pharmacologic blockade of CSE normalized breathing in HO‐2−/− mice. These observations demonstrate that dysregulated CO and H2S signaling in the CB leads to apneas.Support or Funding InformationSupported by NIH‐UH3‐HL90554 and PO1‐HL90554
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