Hydrogen sulfide-based therapeutics and gastrointestinal diseases: translating physiology to treatments

Chan, Melissa; Wallace, John L.

doi:10.1152/ajpgi.00169.2013

Cited by 92 publications

(60 citation statements)

References 76 publications

(121 reference statements)

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“…In addition, H 2 S has been reported to be cytoprotective in some organ systems, such as the central nervous system and gastrointestinal tract, independent of NO (3,11,(16)(17)(18). Although originally considered separate signaling pathways, recent evidence suggests cross-talk between H 2 S and NO signaling in the cardiovascular system.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

King

Polhemus

Bhushan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

330

312

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Previous studies have demonstrated that hydrogen sulfide (H 2 S) protects against multiple cardiovascular disease states in a similar manner as nitric oxide (NO). H 2 S therapy also has been shown to augment NO bioavailability and signaling. The purpose of this study was to investigate the impact of H 2 S deficiency on endothelial NO synthase (eNOS) function, NO production, and ischemia/reperfusion (I/R) injury. We found that mice lacking the H 2 S-producing enzyme cystathionine γ-lyase (CSE) exhibit elevated oxidative stress, dysfunctional eNOS, diminished NO levels, and exacerbated myocardial and hepatic I/R injury. In CSE KO mice, acute H 2 S therapy restored eNOS function and NO bioavailability and attenuated I/R injury. In addition, we found that H 2 S therapy fails to protect against I/R in eNOS phosphomutant mice (S1179A). Our results suggest that H 2 S-mediated cytoprotective signaling in the setting of I/R injury is dependent in large part on eNOS activation and NO generation.eNOS uncoupling | myocardial infarction | cystathionase | Cth | nitrite H ydrogen sulfide (H 2 S), historically known for its odorous smell and toxicity at high concentrations, has recently been classified as a physiological signaling molecule with robust cytoprotective actions in multiple organ systems (1-3). H 2 S is produced enzymatically in mammalian tissues by three different enzymes: cystathionine γ-lyase (CSE), cystathionine beta-synthase (CBS), and 3-mercatopyruvate sulfurtransferase (3-MST). CSE, involved in the cysteine biosynthesis pathway, coordinates with L-cystine to produce H 2 S within the vasculature and is known to regulate blood pressure, modulate cellular metabolism, promote angiogenesis, regulate ion channels, and mitigate fibrosis and inflammation (4). Endothelial nitric oxide synthase (eNOS) catalyzes the production of nitric oxide (NO) from L-arginine within the endothelium to regulate vascular tone via cGMP signaling in vascular smooth muscle, mitochondrial respiration, platelet function, inflammation, and angiogenesis. The biological profiles of H 2 S and NO are similar, and both molecules are known to protect cells against various injurious states that result in organ injury. Although H 2 S and NO are thought to modulate independent signaling pathways, there is limited evidence of cross-talk between these two molecules (5, 6).H 2 S therapeutics and endogenous overexpression of CSE have been shown to attenuate ischemia/reperfusion (I/R) injury (7,8). Similarly, NO therapy and eNOS gene overexpression are also protective in ischemic disease states (9). Given the potent antioxidant actions of H 2 S (10, 11) and the effects of exogenous H 2 S therapy on NO bioavailability (5, 8), we investigated the effects of genetic deletion of the cystathionase gene (Cth, i.e., CSE KO) on the regulation of eNOS function and NO bioavailability. ResultsSulfide Levels are Reduced in CSE KO Mice. Whole blood and heart specimens were collected from WT and CSE KO mice to measure H 2 S levels using a high-sensitivity gas chromato...

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Section: Discussionmentioning

confidence: 99%

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

King

Polhemus

Bhushan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

330

312

View full text Add to dashboard Cite

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“…Cellular H 2 S can be produced by the conversion of cysteine with three enzymes: cystathionine-g-lyase (CSE), cystathionine-b-synthetase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST) [13]. Mutation of H 2 S-producing enzymes result in some disorders such as neural degeneration, skeletal abnormalities, increased risks of thromboembolism, and early onset of atherosclerosis [14]. With H 2 S treatment, the production of adhesion molecules and the proliferation of vascular smooth muscle cells (VSMCs) can be suppressed and then prevents the formation of atherosclerotic lesions [15].…”

Section: Introductionmentioning

confidence: 99%

“…Hence, a fluorescence probe was applied, using the reaction of 4-nitro-7-thiocyanatobenz-2-oxa-1,3-diazole (NBD-SCN) with cysteine and homocysteine [22,25]. The cysteine/homocysteine then can be converted to H 2 S via CSE, CBS and 3-MST [14].…”

Section: Introductionmentioning

confidence: 99%

Laminar shear flow increases hydrogen sulfide and activates a nitric oxide producing signaling cascade in endothelial cells

Huang

Chen

et al. 2015

Biochemical and Biophysical Research Communications

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“…The toxicity of NO has been attributed to the potent nitrating and oxidizing agent, peroxynitrite that affect proteins and DNA. Endogenous H 2 S is produced from L-cysteine either via pyridoxal-5-phosphate (P5P)-dependent enzymes -cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), or the more recently described, cysteine aminotransferase (CAT; also P5P-dependent) and -3-mercaptopyruvatesulfurtransferase (3-MST) pathway (Chan, Wallace, 2013). At physiological conditions H 2 S is produced by gastric mucosa and contributes to gastric ability to resist damage (Yan and Li, 2014), and like NO, it plays a role in modulating gastric inflammatory responses (Aboubakr et al, 2013).…”

Section: +mentioning

confidence: 99%

Interactions between nitric oxide and hydrogen sulfide generating systems in gastric mucosa under condition of the combined action of stress and NDAIDs

Fomenko¹,

Sklyarov²,

Denysenko³

et al. 2017

J App Pharm Sci

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The metabolic relationship between H2S and NO in gastric mucosa in norm and pathology is still poorly studied. Aim of this study was to determine mechanisms of interaction between NO and H2S generating systems under conditions of the combined actions of NSAIDs and stress. Water restraint stress (WRS) was used to induce peptic lessions in rats; naproxen and ATB-346 were administered prior to WRS. Nos2, Cbs and Ptgs2 gene expression level was determined by semiquantitative RT-PCR in gastric epitheliocytes. In the gastric mucosa were determined: alterations in H2S and NOx concentrations, changes in activity of myeloperoxidase. Both WRS and naproxen action prior to WRS cased a significant rise in myeloperoxidase activity. Administration of ATB-346 resulted in a considerable decrease of myeloperoxidase activity. Naproxen action caused the downregulation of Nos2. The level of Cbs expression in group pretreated with naproxen was much higher than in group of WRS alone. We suppose that it increases as a result of Nos2 downregulation and the correspondent decrease of NO concentration. The relationship between NO and H2S in the gastric mucosa is likely mediated through the regulation of genes expression. As a result of the released H2S, ATB-346 administration decreased the severity of gastric mucosa lesions.

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Hydrogen sulfide-based therapeutics and gastrointestinal diseases: translating physiology to treatments

Abstract: Chan MV, Wallace JL. Hydrogen sulfide-based therapeutics and gastrointestinal diseases: translating physiology to treatments.

Cited by 92 publications

References 76 publications

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

Laminar shear flow increases hydrogen sulfide and activates a nitric oxide producing signaling cascade in endothelial cells

Interactions between nitric oxide and hydrogen sulfide generating systems in gastric mucosa under condition of the combined action of stress and NDAIDs

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