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      A tale of two gases: NO and H 2S, foes or friends for life?

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          Abstract

          Nitric oxide (NO) and hydrogen sulfide (H 2S) have emerged as dominant redox regulators of numerous aspects of cellular and physiological functions within several organ systems included cardiovascular, immune and neurological tissues. Recent studies have begun to reveal that these two gaseous molecules may have redundant or overlapping pathophysiological functions often involving similar molecular targets. However, it remains less clear when and how NO and H 2S may interact under biological and disease processes. In this graphical review, we discuss the current understanding of NO and H 2S interactions and how they may functionally influence each other and what this may mean for biology and mechanisms of disease.

          Highlights

          • H 2S and NO are important gaseous regulators of numerous physiological responses.

          • H 2S and NO may target both similar and divergent signaling and molecular pathways.

          • H 2S and NO react with protein free thiols that differentially affect protein function.

          • H 2S and NO metabolites can react together to yield novel biochemical products.

          • The presence and physiological importance of these novel products remains unknown.

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          Most cited references78

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

          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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            Hypertension in mice lacking the gene for endothelial nitric oxide synthase.

            Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is thought to be the endothelium-dependent relaxing factor (EDRF) which mediates vascular relaxation in response to acetylcholine, bradykinin and substance P in many vascular beds. NO has been implicated in the regulation of blood pressure and regional blood flow, and also affects vascular smooth-muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes and hypertension. Pharmacological blockade of NO production with arginine analogues such as L-nitroarginine (L-NA) or L-N-arginine methyl ester affects multiple isoforms of nitric oxide synthase (NOS), and so cannot distinguish their physiological roles. To study the role of endothelial NOS (eNOS) in vascular function, we disrupted the gene encoding eNOS in mice. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, is absent, and the eNOS mutant mice are hypertensive. Thus eNOS mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure.
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              The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide.

              Hydrogen sulfide (H2S), which is well known as a toxic gas, is produced endogenously in mammalian tissues from L-cysteine mainly by two pyridoxal-5'-phosphate-dependent enzymes, cystathionine beta-synthetase and cystathionine gamma-lyase. Recently, we showed that cystathionine beta-synthetase in the brain produces H2S, and that H2S facilitates the induction of hippocampal long-term potentiation by enhancing NMDA receptor activity. Here we show that mRNA for another H2S producing enzyme, cystathionine gamma-lyase, is expressed in the ileum, portal vein, and thoracic aorta. The ileum also expresses cystathionine beta-synthetase mRNA. These tissues produce H2S, and this production is blocked by cystathionine beta-synthetase and cystathionine gamma-lyase specific inhibitors. Although exogenously applied H2S alone relaxed these smooth muscles, much lower concentrations of H2S greatly enhanced the smooth muscle relaxation induced by NO in the thoracic aorta. These observations suggest that the endogenous H2S may regulate smooth muscle tone in synergy with NO.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                23 May 2013
                23 May 2013
                2013
                : 1
                : 1
                : 313-318
                Affiliations
                [a ]Department of Pathology, LSU Health-Shreveport, USA
                [b ]Department of Molecular and Cellular Physiology, LSU Health-Shreveport, USA
                [c ]Department of Cell Biology and Anatomy, LSU Health-Shreveport, USA
                Author notes
                [* ]Corresponding author at: Department of Pathology, LSU Health-Shreveport, USA. Tel./fax:+1 318 675 4694. ckevil@ 123456lsuhsc.edu
                Article
                REDOX44
                10.1016/j.redox.2013.05.001
                3757701
                24024166
                1d88063a-26ba-4842-ae47-1beed121f0eb
                © 2013 The Authors

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 May 2013
                : 9 May 2013
                Categories
                Graphical Review

                thiol,redox biology,cardiovascular disease,vascular biology,chemistry

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