Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function.

Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 08/2011; 108(33):13829-34. DOI: 10.1073/pnas.1105121108
Source: PubMed

ABSTRACT 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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    Biotechnology & Biotechnological Equipment 01/2015; · 0.38 Impact Factor
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    ABSTRACT: Coronary artery disease remains the principal cause of death in patients with diabetes mellitus. Diabetic mice display exacerbated injury following myocardial ischemia-reperfusion (MI/R) and are resistant to most therapeutic interventions. We have reported that sodium sulfide (Na2S) therapy confers cardioprotection during MI/R in non-diabetic mice. Here we tested the hypothesis that Na2S therapy would limit the extent of myocardial injury following MI/R when administered at the time of reperfusion. Diabetic mice (db/db, 12 weeks of age) were subjected to transient myocardial ischemia for a period of 30 minutes followed by reperfusion up to 24 hours. Na2S (0.05 to 1 mg/kg) or saline (vehicle) was administered into the left ventricular lumen at the time of reperfusion. Na2S therapy significantly decreased myocardial injury in the db/db diabetic mouse, as evidenced by a reduction in infarct size and circulating troponin-I levels. The reduction in myocardial injury was also associated with a reduction in oxidative stress and a decrease in cleaved caspase-3 expression. In an effort to evaluate the signaling mechanism responsible for the observed cardioprotection, additional groups of mice were sacrificed during early reperfusion. Hearts were excised and processed for Western blot analysis. These studies revealed that Na2S therapy activated the Erk1/2 arm of the Reperfusion Injury Salvage Kinase (RISK) pathway. These findings provide important information that myocardial Erk1/2 activation by Na2S therapy following MI/R sets into motion events, which ultimately lead to cardioprotection in the setting of diabetes.
    Medical gas research. 01/2014; 4(1):20.
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    Biotechnology & Biotechnological Equipment 01/2015; · 0.38 Impact Factor


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