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      Exogenous Hydrogen Sulfide Inhibits Superoxide Formation, NOX-1 Expression and Rac 1 Activity in Human Vascular Smooth Muscle Cells

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          Abstract

          The activity of NADPH oxidase (NOX) is blocked by nitric oxide (NO). Hydrogen sulfide (H<sub>2</sub>S) is also produced by blood vessels. It is reasonable to suggest that H<sub>2</sub>S may have similar actions to NO on NOX. In order to test this hypothesis, the effect of sodium hydrosulfide (NaHS) on O<sub>2</sub><sup>–</sup> formation, the expression of NOX-1 (a catalytic subunit of NOX) and Rac<sub>1</sub> activity (essential for full NOX activity) in isolated vascular smooth muscle cells (hVSMCs) was investigated. hVSMCs were incubated with the thromboxane A<sub>2</sub> analogue U46619 ± NaHS for 1 or 16 h, and O<sub>2</sub><sup>–</sup> formation, NOX-1 expression and Rac<sub>1</sub> activity were assessed. The possible interaction between H<sub>2</sub>S and NO was also studied by using an NO synthase inhibitor, L-NAME, and an NO donor, DETA-NONOate. The role of K<sub>ATP</sub> channels was studied by using glibenclamide. NaHS inhibited O<sub>2</sub><sup>–</sup> formation following incubation of 1 h (IC<sub>50</sub>, 30 n M) and 16 h (IC<sub>50</sub>, 20 n M), blocked NOX-1 expression and inhibited Rac<sub>1</sub> activity. These inhibitory effects of NaHS were mediated by the cAMP-protein-kinase-A axis. Exogenous H<sub>2</sub>S prevents NOX-driven intravascular oxidative stress through an a priori inhibition of Rac<sub>1</sub> and downregulation of NOX-1 protein expression, an effect mediated by activation of the adenylylcyclase-cAMP-protein-kinase-G system by H<sub>2</sub>S.

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          Most cited references 32

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          The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener.

          Hydrogen sulfide (H(2)S) has been traditionally viewed as a toxic gas. It is also, however, endogenously generated from cysteine metabolism. We attempted to assess the physiological role of H(2)S in the regulation of vascular contractility, the modulation of H(2)S production in vascular tissues, and the underlying mechanisms. Intravenous bolus injection of H(2)S transiently decreased blood pressure of rats by 12- 30 mmHg, which was antagonized by prior blockade of K(ATP) channels. H(2)S relaxed rat aortic tissues in vitro in a K(ATP) channel-dependent manner. In isolated vascular smooth muscle cells (SMCs), H(2)S directly increased K(ATP) channel currents and hyperpolarized membrane. The expression of H(2)S-generating enzyme was identified in vascular SMCs, but not in endothelium. The endogenous production of H(2)S from different vascular tissues was also directly measured with the abundant level in the order of tail artery, aorta and mesenteric artery. Most importantly, H(2)S production from vascular tissues was enhanced by nitric oxide. Our results demonstrate that H(2)S is an important endogenous vasoactive factor and the first identified gaseous opener of K(ATP) channels in vascular SMCs.
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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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              Regulation of NADPH oxidases: the role of Rac proteins.

               Peter Hordijk (2006)
              The role for reactive oxygen species (ROS) in cellular (patho)physiology, in particular in signal transduction, is increasingly recognized. The family of NADPH oxidases (NOXes) plays an important role in the production of ROS in response to receptor agonists such as growth factors or inflammatory cytokines that signal through the Rho-like small GTPases Rac1 or Rac2. The phagocyte oxidase (gp91phox/NOX2) is the best characterized family member, and its mode of activation is relatively well understood. Recent work has uncovered novel and increasingly complex modes of control of the NOX2-related proteins. Some of these, including NOX2, have been implicated in various aspects of (cardio)vascular disease, including vascular smooth muscle and endothelial cell hypertrophy and proliferation, inflammation, and atherosclerosis. This review focuses on the role of the Rac1 and Rac2 GTPases in the activation of the various NOX family members.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2008
                October 2008
                07 May 2008
                : 45
                : 6
                : 521-528
                Affiliations
                aBristol Heart Institute, University of Bristol, Bristol, UK; bIstituto di Chimica Farmaceutica e Tossicologica, University of Milan, and cCTG Pharma SRL, Milan, Italy
                Article
                129686 J Vasc Res 2008;45:521–528
                10.1159/000129686
                18463417
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 7, References: 43, Pages: 8
                Categories
                Research Paper

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