Abstract 17911: Genetic Overexpression of the Hydrogen Sulfide Producing Enzyme Cystathionine gama-Lyase in Endothelial Cells Enhances Hydrogen Sulfide and Nitric Oxide Signaling
Background: Endogenous generation of H2S is critical for cardiovascular homeostasis. H2S deficiency associated with cardiovascular disease disrupts NO signaling via dysregulation of endothelial nitric oxide synthase. Cystathionine gama-lyase (CSE) is one of three known H2S producing enzymes that regulates H2S biovailability and cardiovascular function.
Hypothesis: Genetic overexpression of CSE in endothelial cells will upregulate H2S and NO bioavailability and signaling.
Methods and Results: Endothelial cell-specific CSE transgenic (EC-CSE Tg) mice and tTA control mice (n = 7 - 9 per group) were sacrificed at 9-11 weeks of age and blood and heart tissue were collected. Plasma and myocardial H2S and sulfane sulfur levels were determined using gas chromatography and sulfur chemiluminescence (Aligent). Plasma and myocardial nitrite level were quantified by ion chromatography (Eicom). EC-CSE Tg mice had significantly elected levels of free H2S in plasma compared to the tTA control mice (0.28 ± 0.02 vs. 0.15 ± 0.04 μM, p < 0.05), but we did not observe any change in myocardial free H2S level (5.0 ± 0.11 vs. 4.6 ± 0.19 nmol/mg, p = NS). The storage form of H2S, sulfane sulfur was significantly elevated in the circulation (0.69 ± 0.03 vs. 0.36 ± 0.04 μM, p < 0.001) and myocardial tissue (83.16 ± 6.7 vs. 42.47 ± 9.4 nmol/mg) in EC-CSE Tg mice compared to tTA control mice. Nitrite levels were also significantly elevated in both circulation (0.47 ± 0.02 vs. 0.36 ± 0.03 μM, p < 0.05 vs. tTA control) and myocardial tissue (0.35 ± 0.04 vs. 0.24 ± 0.02 μM, p < 0.05 vs. tTA control) indicating increased NO bioavailability.
Conclusion: Overexpression of CSE in endothelial cells significantly augments circulating and myocardial H2S and NO bioavailability and signaling. This study reports, for the first time that overexpression of CSE enhances NO signaling beyond basal levels. Endothelial cell generated H2S production may be a potential therapeutic target for treating cardiovascular diseases.
Author Disclosures: Z. Li: None. D.J. Polhemus: None. C.L. Organ: None. J.W. Elrod: None. D.J. Lefer: None.
- © 2016 by American Heart Association, Inc.