Complementary roles of gasotransmitters CO and H2S in sleep apnea

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Abstract

The carotid body (CB) is the major sensory organ responsible for monitoring arterial blood oxygen content. Glomus cells in the CB express heme oxygenase 2 (HO-2) and cystathionine-γ-lyase (CSE), enzymes that generate the gasotransmitters carbon monoxide (CO) and hydrogen sulfide (H 2S), respectively. In normoxia, CO inhibits CSE from producing H 2S. During hypoxia, HO-2 produces less CO, resulting in increased H 2S production, which stimulates CB activity, leading to increases in respiratory rate, heart rate, and blood pressure. We report that decreased CO and increased H 2S generation in the CB causes sleep apnea in HO-2 knockout mice and spontaneously hypertensive rats. An inhibitor of CSE eliminates sleep apnea when administered to these animals, suggesting that this approach may have therapeutic utility in patients with sleep apnea. 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 (H 2S) as the major effector molecule driving apneas. Genetic ablation of the H 2S-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 H 2S signaling in the CB leads to apneas and suggest that CSE inhibition may be a useful therapeutic intervention for preventing CB-driven sleep apnea.

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Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets.

Danny J Eckert, David P White, Amy S. Jordan … (2013)

The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized. To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA. Seventy-five men and women with and without OSA aged 20-65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway [Pcrit]) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA. Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, and 36% had high loop gain. A total of 28% had multiple nonanatomic features. Although overall the upper airway was more collapsible in patients with OSA (Pcrit, 0.3 [-1.5 to 1.9] vs. -6.2 [-12.4 to -3.6] cm H2O; P <0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, -2 to -5 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than -2 cm H2O (-5.9 [-8.8 to -4.5] vs. -3.2 [-4.8 to -2.4] dimensionless; P = 0.01). A three-point scale for weighting the relative contribution of the traits is proposed. It suggests that nonanatomic features play an important role in 56% of patients with OSA. This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.

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Wild type microglia arrest pathology in a mouse model of Rett syndrome

Noël C. Derecki, James Cronk, Zhenjie Lu … (2012)

Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in the majority of cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein 1–5 . Although MeCP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction 6 . However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examined the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of Mecp2 in myeloid cells, driven by Lysmcre on an Mecp2-null background, dramatically attenuated disease symptoms. Thus, via multiple approaches, wild type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology; lifespan was increased; breathing patterns were normalized; apneas were reduced; body weight was increased to near wild type, and locomotor activity was improved. Mecp2 +/− females also exhibited significant improvements as a result of wild type microglial engraftment. These benefits mediated by wild type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in Rett pathophysiology, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for this devastating disorder.

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Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE)

Antonia Asimakopoulou, Panagiotis Panopoulos, Christos Chasapis … (2013)

BACKGROUND AND PURPOSE Hydrogen sulfide (H2S) is a signalling molecule that belongs to the gasotransmitter family. Two major sources for endogenous enzymatic production of H2S are cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). In the present study, we examined the selectivity of commonly used pharmacological inhibitors of H2S biosynthesis towards CSE and CBS. EXPERIMENTAL APPROACH To address this question, human CSE or CBS enzymes were expressed and purified from Escherichia coli as fusion proteins with GSH-S-transferase. After purification, the activity of the recombinant enzymes was tested using the methylene blue method. KEY RESULTS β-cyanoalanine (BCA) was more potent in inhibiting CSE than propargylglycine (PAG) (IC50 14 ± 0.2 μM vs. 40 ± 8 μM respectively). Similar to PAG, L-aminoethoxyvinylglycine (AVG) only inhibited CSE, but did so at much lower concentrations. On the other hand, aminooxyacetic acid (AOAA), a frequently used CBS inhibitor, was more potent in inhibiting CSE compared with BCA and PAG (IC50 1.1 ± 0.1 μM); the IC50 for AOAA for inhibiting CBS was 8.5 ± 0.7 μM. In line with our biochemical observations, relaxation to L-cysteine was blocked by AOAA in aortic rings that lacked CBS expression. Trifluoroalanine and hydroxylamine, two compounds that have also been used to block H2S biosynthesis, blocked the activity of CBS and CSE. Trifluoroalanine had a fourfold lower IC50 for CBS versus CSE, while hydroxylamine was 60-fold more selective against CSE. CONCLUSIONS AND IMPLICATIONS In conclusion, although PAG, AVG and BCA exhibit selectivity in inhibiting CSE versus CBS, no selective pharmacological CBS inhibitor is currently available.