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      Hydrogen Sulfide as a Novel Regulatory Factor in Liver Health and Disease

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          Abstract

          Hydrogen sulfide (H 2S), a colorless gas smelling of rotten egg, has long been recognized as a toxic gas and environment pollutant. However, increasing evidence suggests that H 2S acts as a novel gasotransmitter and plays important roles in a variety of physiological and pathological processes in mammals. H 2S is involved in many hepatic functions, including the regulation of oxidative stress, glucose and lipid metabolism, vasculature, mitochondrial function, differentiation, and circadian rhythm. In addition, H 2S contributes to the pathogenesis and treatment of a number of liver diseases, such as hepatic fibrosis, liver cirrhosis, liver cancer, hepatic ischemia/reperfusion injury, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, hepatotoxicity, and acute liver failure. In this review, the biosynthesis and metabolism of H 2S in the liver are summarized and the role and mechanism of H 2S in liver health and disease are further discussed.

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          H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase.

          Guangdong Yang, Lingyun Wu, Bo Jiang … (2008)
          Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H2S) is now receiving increasing attention. Here we show that H2S is physiologically generated by cystathionine gamma-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H2S formation in response to vascular activation. These findings provide direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure.
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            Hydrogen sulfide is an endogenous stimulator of angiogenesis.

            Andreas Papapetropoulos, Anastasia Pyriochou, Zaid Altaany … (2009)
            The goal of the current study was to investigate the role of exogenous and endogenous hydrogen sulfide (H(2)S) on neovascularization and wound healing in vitro and in vivo. Incubation of endothelial cells (ECs) with H(2)S enhanced their angiogenic potential, evidenced by accelerated cell growth, migration, and capillary morphogenesis on Matrigel. Treatment of chicken chorioallantoic membranes (CAMS) with H(2)S increased vascular length. Exposure of ECs to H(2)S resulted in increased phosphorylation of Akt, ERK, and p38. The K(ATP) channel blocker glibenclamide or the p38 inhibitor SB203580 abolished H(2)S-induced EC motility. Since glibenclamide inhibited H(2)S-triggered p38 phosphorylation, we propose that K(ATP) channels lay upstream of p38 in this process. When CAMs were treated with H(2)S biosynthesis inhibitors dl-propylargylglycine or beta-cyano-L-alanine, a reduction in vessel length and branching was observed, indicating that H(2)S serves as an endogenous stimulator of the angiogenic response. Stimulation of ECs with vascular endothelial growth factor (VEGF) increased H(2)S release, while pharmacological inhibition of H(2)S production or K(ATP) channels or silencing of cystathionine gamma-lyase (CSE) attenuated VEGF signaling and migration of ECs. These results implicate endothelial H(2)S synthesis in the pro-angiogenic action of VEGF. Aortic rings isolated from CSE knockout mice exhibited markedly reduced microvessel formation in response to VEGF when compared to wild-type littermates. Finally, in vivo, topical administration of H(2)S enhanced wound healing in a rat model, while wound healing was delayed in CSE(-/-) mice. We conclude that endogenous and exogenous H(2)S stimulates EC-related angiogenic properties through a K(ATP) channel/MAPK pathway.
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              Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer.

              C. Szabo, C. Coletta, C. Chao … (2013)
              The physiological functions of hydrogen sulfide (H2S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective up-regulation of the H2S-producing enzyme cystathionine-β-synthase (CBS) in colon cancer, resulting in an increased rate of H2S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS up-regulation and increased H2S production, compared with the nonmalignant colonic mucosa cells, NCM356. CBS localized to the cytosol, as well as the mitochondrial outer membrane. ShRNA-mediated silencing of CBS or its pharmacological inhibition with aminooxyacetic acid reduced HCT116 cell proliferation, migration, and invasion; reduced endothelial cell migration in tumor/endothelial cell cocultures; and suppressed mitochondrial function (oxygen consumption, ATP turnover, and respiratory reserve capacity), as well as glycolysis. Treatment of nude mice with aminooxyacetic acid attenuated the growth of patient-derived colon cancer xenografts and reduced tumor blood flow. Similarly, CBS silencing of the tumor cells decreased xenograft growth and suppressed neovessel density, suggesting a role for endogenous H2S in tumor angiogenesis. In contrast to CBS, silencing of cystathionine-γ-lyase (the expression of which was unchanged in colon cancer) did not affect tumor growth or bioenergetics. In conclusion, H2S produced from CBS serves to (i) maintain colon cancer cellular bioenergetics, thereby supporting tumor growth and proliferation, and (ii) promote angiogenesis and vasorelaxation, consequently providing the tumor with blood and nutritients. The current findings identify CBS-derived H2S as a tumor growth factor and anticancer drug target.
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                Author and article information

                Journal
                Title: Oxidative Medicine and Cellular Longevity
                Abbreviated Title: Oxidative Medicine and Cellular Longevity
                Publisher: Hindawi Limited
                ISSN (Print): 1942-0900
                ISSN (Electronic): 1942-0994
                Publication date Created: January 20 2019
                Publication date (Print): January 20 2019
                Volume: 2019
                Pages: 1-16
                Affiliations
                [1 ]School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
                [2 ]Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, Henan 475004, China
                [3 ]The First Affiliated Hospital of Henan University, Kaifeng, Henan 475001, China
                [4 ]Center for Precision Medicine, Zhengzhou University, Zhengzhou, Henan 450052, China
                [5 ]Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, Henan 475004, China
                Article
                DOI: 10.1155/2019/3831713
                SO-VID: c3e20d4a-d85a-4cdd-ae49-fa3441bdfa36
                Copyright © © 2019
                License:

                http://creativecommons.org/licenses/by/4.0/

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