Suzuki K, Olah G, Modis K et al.Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function. Proc Natl Acad Sci USA 108:13829-13834

Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2011; 108(33):13829-34. DOI: 10.1073/pnas.1105121108
Source: PubMed


The goal of the present studies was to investigate the role of changes in hydrogen sulfide (H(2)S) homeostasis in the pathogenesis of hyperglycemic endothelial dysfunction. Exposure of bEnd3 microvascular endothelial cells to elevated extracellular glucose (in vitro "hyperglycemia") induced the mitochondrial formation of reactive oxygen species (ROS), which resulted in an increased consumption of endogenous and exogenous H(2)S. Replacement of H(2)S or overexpression of the H(2)S-producing enzyme cystathionine-γ-lyase (CSE) attenuated the hyperglycemia-induced enhancement of ROS formation, attenuated nuclear DNA injury, reduced the activation of the nuclear enzyme poly(ADP-ribose) polymerase, and improved cellular viability. In vitro hyperglycemia resulted in a switch from oxidative phosphorylation to glycolysis, an effect that was partially corrected by H(2)S supplementation. Exposure of isolated vascular rings to high glucose in vitro induced an impairment of endothelium-dependent relaxations, which was prevented by CSE overexpression or H(2)S supplementation. siRNA silencing of CSE exacerbated ROS production in hyperglycemic endothelial cells. Vascular rings from CSE(-/-) mice exhibited an accelerated impairment of endothelium-dependent relaxations in response to in vitro hyperglycemia, compared with wild-type controls. Streptozotocin-induced diabetes in rats resulted in a decrease in the circulating level of H(2)S; replacement of H(2)S protected from the development of endothelial dysfunction ex vivo. In conclusion, endogenously produced H(2)S protects against the development of hyperglycemia-induced endothelial dysfunction. We hypothesize that, in hyperglycemic endothelial cells, mitochondrial ROS production and increased H(2)S catabolism form a positive feed-forward cycle. H(2)S replacement protects against these alterations, resulting in reduced ROS formation, improved endothelial metabolic state, and maintenance of normal endothelial function.

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    • "This difference could be explained with decreased levels of H 2 S as a result of induction of diabetes. Thus, Whiteman et al. [34] and Jain et al. [35] reported that diabetes is associated with lower circulating levels of H 2 S. It is also known that rats with STZ-induced diabetes exhibit a decrease in their blood H 2 S concentrations without any change in the tissue expression of CSE.[36] In a further research, we applied PGG to block H 2 S synthesis.[25] "
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    ABSTRACT: 2014): Cystathionine gamma-lyase of perivascular adipose tissue with reversed regulatory effect in diabetic rat artery, Biotechnology & Biotechnological Equipment, makes every effort to ensure the accuracy of all the information (the "Content") contained in the publications on our platform. Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Versions of published Taylor & Francis and Routledge Open articles and Taylor & Francis and Routledge Open Select articles posted to institutional or subject repositories or any other third-party website are without warranty from Taylor & Francis of any kind, either expressed or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. Any opinions and views expressed in this article are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor & Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Terms & Conditions of access and use can be found at It is essential that you check the license status of any given Open and Open Select article to confirm conditions of access and use.
    Biotechnology & Biotechnological Equipment 01/2015; DOI:10.1080/13102818.2014.991565 · 0.30 Impact Factor
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    • "Emerging mitochondrial roles of hydrogen sulfide (H 2 S) include antioxidant effects, modulation of mitochondrial cell death pathways and the regulation of cellular bioenergetics reviewed in [1] [2] [3] [4]. With respect to antioxidant/cell death modulating responses, multiple studies have demonstrated that H 2 S donors can maintain mitochondrial integrity, reduce the release of mitochondrial death signals and attenuate mitochondrially-regulated cell death responses of various types [5] [6] [7] [8] [9] [10] [11] [12] [13]. With respect to the regulatory role of H 2 S on cellular bioenergetic responses, recent data show that H 2 S, in lower concentrations, serves as a physiological electron donor and as an inorganic source of energy in mammalian cells; via these pathways, H 2 S acts as an alternative supporter of mitochondrial electron transport and ATP generation [4,14–17]. "
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    ABSTRACT: The purpose of the current study was to investigate the effect of the recently synthesized mitochondrially-targeted H2S donor, AP39 [10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], on bioenergetics, viability, and mitochondrial DNA integrity in bEnd.3 murine microvascular endothelial cells in vitro, under normal conditions, and during oxidative stress. Intracellular H2S was assessed by the fluorescent dye 7-azido-4-methylcoumarin. For the measurement of bioenergetic function, the XF24 Extracellular Flux Analyzer was used. Cell viability was estimated by the combination of the MTT and LDH methods. Oxidative protein modifications were measured by the Oxyblot method. Reactive oxygen species production was monitored by the MitoSOX method. Mitochondrial and nuclear DNA integrity were assayed by the Long Amplicon PCR method. Oxidative stress was induced by addition of glucose oxidase. AP39 (30 - 300 nM) to bEnd.3 cells increased intracellular H2S levels, with a preferential response in the mitochondrial regions. AP39 exerted a concentration-dependent effect on mitochondrial activity, which consisted of a stimulation of mitochondrial electron transport and cellular bioenergetic function at lower concentrations (30-100 nM) and an inhibitory effect at the higher concentration of 300 nM. Under oxidative stress conditions induced by glucose oxidase, an increase in oxidative protein modification and an enhancement in MitoSOX oxidation was noted, coupled with an inhibition of cellular bioenergetic function and a reduction in cell viability. AP39 pretreatment attenuated these responses. Glucose oxidase induced a preferential damage to the mitochondrial DNA; AP39 (100 nM) pretreatment protected against it. In conclusion, the current paper documents antioxidant and cytoprotective effects of AP39 under oxidative stress conditions, including a protection against oxidative mitochondrial DNA damage.
    Nitric Oxide 04/2014; 41. DOI:10.1016/j.niox.2014.04.008 · 3.52 Impact Factor
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    • "leasing H 2 S donors on stroke outcomes . Another drawback of current studies about H 2 S roles in stroke is that these studies exclusively focus on H 2 S effects on stroke - induced parenchyma injury , especially neuronal injury . Although H 2 S is increasingly recognized to be beneficial to vascular health under various pathological conditions ( Suzuki et al . 2011 ; Wen et al . 2013 ) and although recent stroke studies emphasize the importance of neurovascular protection , surprisingly , whether H 2 S confers vasoprotection against BBB damage following stroke has not been investigated ."
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    ABSTRACT: By using two structurally unrelated hydrogen sulfide (H2S) donors 5-(4-methoxyphenyl) -3H-1, 2-dithiole-3-thione (ADT) and sodium hydrosulfide (NaHS), this study investigated if H2S protected blood-brain barrier (BBB) integrity following middle cerebral artery occlusion (MCAO). ICR mice underwent MCAO and received H2S donors at 3 h after reperfusion. Infarction, neurological scores, brain edema, Evans blue (EB) extravasation, and tight junction protein expression were examined at 48 h after MCAO. We also investigated if ADT protected BBB integrity by suppressing post-ischemic inflammation-induced Matrix Metalloproteimase-9 (MMP9) and Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). ADT increased blood H2S concentrations, decreased infarction, and improved neurological deficits. Particularly, ADT reduced EB extravasation, brain edema and preserved expression of tight junction proteins in the ischemic brain. NaHS also increased blood H2S levels and reduced EB extravasation following MCAO. Moreover, ADT inhibited expression of pro-inflammatory markers induced Nitric Oxide Synthase (iNOS) and IL-1β while enhanced expression of anti-inflammatory markers arginase 1 and IL-10 in the ischemic brain. Accordingly, ADT attenuated ischemia-induced expression and activity of MMP9. Moreover, ADT reduced NOX-4 mRNA expression, NOX activity, and inhibited nuclear translocation of Nuclear Factor Kappa-B (NF-κB) in the ischemic brain. In conclusion, H2S donors protected BBB integrity following experimental stroke possibly by acting through NF-κB inhibition to suppress neuroinflammation induction of MMP9 and NOX4-derived free radicals.
    Journal of Neurochemistry 02/2014; 129(5). DOI:10.1111/jnc.12695 · 4.28 Impact Factor
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