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Anti-atherogenic effect of hydrogen sulfide by over-expression of cystathionine gamma-lyase (CSE) gene.

Cheung SH, Kwok WK, To KF, Lau JY - PLoS ONE (2014)

Bottom Line: They were then fed with either normal or atherogenic diet for 12 weeks.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.

ABSTRACT
Hydrogen sulfide (H2S) is an important gaseous signaling molecule that functions in physiological and pathological conditions, such as atherosclerosis. H2S dilates vessels and therefore has been suggested as an anti-atherogenic molecule. Since cystathionine gamma-lyase (CSE) enzyme is responsible for producing H2S in the cardiovascular system, we hypothesized that up-regulation of CSE expression in vivo with preservation of H2S 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 H2S 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 H2S by CSE gene activation was associated with reduced atherosclerosis in ApoE-deficient mice. Up-regulation of CSE/H2S pathway attenuates atherosclerosis and this would be a potential target for therapeutic intervention against its formation.

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Increased plasma level of adipinectin in CSE transgenic ApoE-KO (Tg/KO) mice.(A) Plasma adiponectin level (n = 6) was higher in Tg/KO mice when compared to the KO mice in both diets. (B) Relationship between plasma level of adiponectin and H2S production rate was positively correlated.
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pone-0113038-g005: Increased plasma level of adipinectin in CSE transgenic ApoE-KO (Tg/KO) mice.(A) Plasma adiponectin level (n = 6) was higher in Tg/KO mice when compared to the KO mice in both diets. (B) Relationship between plasma level of adiponectin and H2S production rate was positively correlated.

Mentions: With the increase of endogenous H2S, plasma total cholesterol (Figure 4A), LDL/VLDL cholesterol (Figure 4B) and triglyceride (Figure 4C) levels were lowered by 24.1%, 23.1% and 40.7% in respectively in mice fed with normal diet. In mice fed with atherogenic diet, the corresponding decrease were 34.1%, 17.4% and 26.3% respectively. Figure 4D showed that there was a significant negative relationship between aortic CSE expression level and both total cholesterol and LDL/VLDL cholesterol. However, its relationship with triglyceride was not statistically significant. Tg/KO mice were found to have higher plasma adiponectin level as compared to KO mice (Figure 5A). The plasma adiponectin level was positively correlated to the H2S production (Figure 5B). On the other hand, it was expected that the oxidative stress would be reduced due to the reduced level of LDL/VLDL cholesterol. Therefore, plasma glutathione peroxidase (GPx) activity was determined. In association with attenuation of lipids, markedly elevated plasma GPx activity (Figure 6A), glutathione (GSH) (Figure 6B) and total glutathione/oxidized glutathione (GSH and GSSG) (Figure 6C) were observed in Tg/KO mice fed with both diets, demonstrating that cells are protected from oxidative damages. Overexpression of CSE can help improving plasma lipids and reducing oxidative stress.


Anti-atherogenic effect of hydrogen sulfide by over-expression of cystathionine gamma-lyase (CSE) gene.

Cheung SH, Kwok WK, To KF, Lau JY - PLoS ONE (2014)

Increased plasma level of adipinectin in CSE transgenic ApoE-KO (Tg/KO) mice.(A) Plasma adiponectin level (n = 6) was higher in Tg/KO mice when compared to the KO mice in both diets. (B) Relationship between plasma level of adiponectin and H2S production rate was positively correlated.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4232559&req=5

pone-0113038-g005: Increased plasma level of adipinectin in CSE transgenic ApoE-KO (Tg/KO) mice.(A) Plasma adiponectin level (n = 6) was higher in Tg/KO mice when compared to the KO mice in both diets. (B) Relationship between plasma level of adiponectin and H2S production rate was positively correlated.
Mentions: With the increase of endogenous H2S, plasma total cholesterol (Figure 4A), LDL/VLDL cholesterol (Figure 4B) and triglyceride (Figure 4C) levels were lowered by 24.1%, 23.1% and 40.7% in respectively in mice fed with normal diet. In mice fed with atherogenic diet, the corresponding decrease were 34.1%, 17.4% and 26.3% respectively. Figure 4D showed that there was a significant negative relationship between aortic CSE expression level and both total cholesterol and LDL/VLDL cholesterol. However, its relationship with triglyceride was not statistically significant. Tg/KO mice were found to have higher plasma adiponectin level as compared to KO mice (Figure 5A). The plasma adiponectin level was positively correlated to the H2S production (Figure 5B). On the other hand, it was expected that the oxidative stress would be reduced due to the reduced level of LDL/VLDL cholesterol. Therefore, plasma glutathione peroxidase (GPx) activity was determined. In association with attenuation of lipids, markedly elevated plasma GPx activity (Figure 6A), glutathione (GSH) (Figure 6B) and total glutathione/oxidized glutathione (GSH and GSSG) (Figure 6C) were observed in Tg/KO mice fed with both diets, demonstrating that cells are protected from oxidative damages. Overexpression of CSE can help improving plasma lipids and reducing oxidative stress.

Bottom Line: They were then fed with either normal or atherogenic diet for 12 weeks.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.

ABSTRACT
Hydrogen sulfide (H2S) is an important gaseous signaling molecule that functions in physiological and pathological conditions, such as atherosclerosis. H2S dilates vessels and therefore has been suggested as an anti-atherogenic molecule. Since cystathionine gamma-lyase (CSE) enzyme is responsible for producing H2S in the cardiovascular system, we hypothesized that up-regulation of CSE expression in vivo with preservation of H2S 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 H2S 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 H2S by CSE gene activation was associated with reduced atherosclerosis in ApoE-deficient mice. Up-regulation of CSE/H2S pathway attenuates atherosclerosis and this would be a potential target for therapeutic intervention against its formation.

Show MeSH
Related in: MedlinePlus