Anti-Atherogenic Effect of Hydrogen Sulfide by Over-Expression of Cystathionine Gamma-Lyase (CSE) Gene

Hydrogen sulfide (H(2)S) is an important gaseous signaling molecule that functions in physiological and pathological conditions, such as atherosclerosis. H(2)S dilates vessels and therefore has been suggested as an anti-atherogenic molecule. Since cystathionine gamma-lyase (CSE) enzyme is responsible for producing H(2)S in the cardiovascular system, we hypothesized that up-regulation of CSE expression in vivo with preservation of H(2)S bioactivity can slow down plaque formation and, can serve as a therapeutic strategy against atherosclerosis. In this study, C57BL/6 wild type mice (WT), ApoE knockout mice (KO) and transgenic ApoE knockout mice overexpressing CSE (Tg/KO) at four weeks of age were weaned. They were then fed with either normal or atherogenic diet for 12 weeks. At week 16, serial plasma lipid levels, body weight, and blood pressure were measured prior to euthanization of the mice and the size of atherosclerotic plaques at their aortic roots was measured. Tg/KO mice showed an increase in endogenous H(2)S production in aortic tissue, reduced atherosclerotic plaque sizes and attenuation in plasma lipid profiles. We also showed an up-regulation in plasma glutathionine peroxidase that could indicate reduced oxidative stress. Furthermore, there was an increase in expression of p-p53 and down regulation of inflammatory nuclear factor-kappa B (NF-κB) in aorta. To conclude, alteration of endogenous H(2)S by CSE gene activation was associated with reduced atherosclerosis in ApoE-deficient mice. Up-regulation of CSE/H(2)S pathway attenuates atherosclerosis and this would be a potential target for therapeutic intervention against its formation.