Article

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.

0 Followers
 · 
160 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes-induced kidney cell injury involves increase in matrix protein expression that is only partly alleviated by current treatment, prompting a search for new modalities. We have previously shown that hydrogen sulfide (H2S) inhibits high glucose-induced protein synthesis in kidney podocytes. We tested if tadalafil, a phosphodiesterase 5 (PDE5) inhibitor used to treat erectile dysfunction, ameliorates high glucose stimulation of matrix proteins by generating H2S in podocytes. Tadalafil abrogated high glucose stimulation of global protein synthesis and matrix protein, laminin γ1. Tadalafil inhibited high glucose-induced activation of mTORC1 and laminin γ1 accumulation in an AMP-activated protein kinase (AMPK)-dependent manner. Tadalafil increased AMPK phosphorylation by stimulating Calcium calmodulin kinase kinaseβ. Tadalafil rapidly increased the expression and activity of H2S generating enzyme, cystathionine-γ-lyase (CSE), by promoting its translation. DL-propargylglycine, a CSE inhibitor, and siRNA of CSE inhibited tadalafil-induced AMPK phosphorylation and abrogated tadalafil effect on high glucose stimulation of laminin γ1. In tadalafil treated podocytes, we examined the interaction between H2S and nitric oxide (NO). L-NAME and ODQ, inhibitors of NO synthase (NOS) and soluble guanylyl cyclase, respectively, abolished tadalafil induction of H2S and AMPK phosphorylation. Tadalafil rapidly augmented inducible NOS (iNOS) expression by increasing its mRNA; siRNA of iNOS and 1400W, an iNOS blocker, inhibited tadalafil stimulation of CSE expression and AMPK phosphorylation. We conclude that tadalafil amelioration of high glucose stimulation of synthesis of proteins including matrix proteins in podocytes requires integration of NO-H2S-AMPK axis leading to the inhibition of high glucose-induced mTORC1 activity and mRNA translation. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; 290(19). DOI:10.1074/jbc.M114.615377 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Determining the levels of endogenous hydrogen sulphide in real time has become increasingly crucial because of its important biological roles in various physiological and pathological processes. Optical methods allowing sensitive, multiplex and dynamic analysis in a non-invasive manner have attracted much attention in biological and biomedical analysis. This review provides an overview of recent advancements in optical analysis of biological hydrogen sulphide, with a focus on fluorescent and non-fluorescent optical strategies for sensing and imaging subcellular hydrogen sulphide in living biosystems.
    The Analyst 01/2015; 140(6). DOI:10.1039/C4AN02204A · 3.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The physiological and pathological roles of hydrogen sulfide (H2S) in the regulation of cardiovascular functions have been recognized. Cystathionine gamma-lyase (CSE) is a major H2S-producing enzyme in cardiovascular system. Ischemic post-conditioning (PC) provides cadioprotection in young hearts but lost in the aging hearts. The involvement of H2S in the recovery of PC-induced cardioprotection in the aging hearts is unclear. In the present study, we demonstrated that ischemia/reperfusion (I/R) decreased H2S production rate and CSE expression, aggravated cardiomyocytes damage, apoptosis and myocardial infarct size, reduced cardiac function, increased the levels of Bcl-2, caspase-3 and caspase-9 mRNA, enhanced oxidative stress in isolated young and aging rat hearts. I/R also increased the release of cytochrome c and down-regulated the phosphorylation of PI3K, Akt and GSK-3β in the aging rat hearts. We further found that PC increased H2S production rate and CSE expressions, and protected young hearts from I/R-induced cardiomyocytes damage, all of which were disappeared in the aging hearts. Supply of NaHS not only increased PC-induced cardioprotection in the young hearts, but also lightened I/R induced-myocardial damage and significantly recovered the cardioprotective role of PC against I/R induced myocardial damage in the aging hearts. LY294002 (a PI3K inhibitor) abolished but N-acetyl-cysteine (NAC, an inhibitor of reactive oxygen species, ROS) further enhanced the protective role of H2S against I/R induced myocardial damage in the aging hearts. In conclusion, these results demonstrate that exogenous H2S recovers PC-induced cardioprotection via inhibition of oxidative stress and up-regulation of PI3K-Akt-GSK-3β pathway in the aging rat hearts. These findings suggested that H2S might be a novel target for the treatment of aging cardiovascular diseases.
    12/2015; 5(1):11. DOI:10.1186/s13578-015-0003-4

Full-text

Download
112 Downloads
Available from
May 23, 2014