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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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Anti-atherogenic effect of CSE gene activation with higher H2S production.(A) Plasma total cholesterol (n = 8 to 10), (B) LDL/VLDL cholesterol (n = 8 to 10) and (C) triglyceride level (n = 6) were significantly reduced in Tg/KO mice after feeding with 12 weeks of normal diet or atherogenic diet when comparing to KO mice. (D) Relationship between aortic CSE mRNA expression level and levels of plasma lipids. There was a significant negative relationship between CSE mRNA expression and levels of total cholesterol and LDL/VLDL cholesterol. However, its relationship with triglyceride was not statistically significant.
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pone-0113038-g004: Anti-atherogenic effect of CSE gene activation with higher H2S production.(A) Plasma total cholesterol (n = 8 to 10), (B) LDL/VLDL cholesterol (n = 8 to 10) and (C) triglyceride level (n = 6) were significantly reduced in Tg/KO mice after feeding with 12 weeks of normal diet or atherogenic diet when comparing to KO mice. (D) Relationship between aortic CSE mRNA expression level and levels of plasma lipids. There was a significant negative relationship between CSE mRNA expression and levels of total cholesterol and LDL/VLDL cholesterol. However, its relationship with triglyceride was not statistically significant.

Mentions: During the 12 weeks of diet treatment, both KO and Tg/KO mice increased in their body weight. But their weight gain was significantly reduced once the diets switched from normal to atherogenic at 4 weeks of age (Figure 3A). When comparing Tg/KO mice with KO mice with the same diet, the average weight gain by Tg/KO mice was significant less by about 3 grams (Figure 3A). To demonstrate whether caloric restriction Tg/KO mice could account for cardioprotective effect, food consumption by KO and Tg/KO mice was measured (Table S2). Both KO and Tg/KO mice consumed less in atherogenic diet (Figure 3B). Moreover, the two groups did not differ in the amount of food intake (Figure 3B). Since KO mice shows hypertension in comparison with WT mice groups, it was suspected that overexpression of CSE may lower blood pressure or even cause hypotension in Tg/KO mice. As shown in Figure 3C, CSE gene activation did not significantly change the blood pressure of Tg/KO mice fed with either normal or atherogenic diets. CSE does not appear to affect blood pressure in these mice. Instead, blood pressure seemed to be affected by the level of cholesterol. As shown in Figure 4A, although the total cholesterol of Tg/KO mice was reduced when compared to the KO mice, it was not as low as that of the WT mice.


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)

Anti-atherogenic effect of CSE gene activation with higher H2S production.(A) Plasma total cholesterol (n = 8 to 10), (B) LDL/VLDL cholesterol (n = 8 to 10) and (C) triglyceride level (n = 6) were significantly reduced in Tg/KO mice after feeding with 12 weeks of normal diet or atherogenic diet when comparing to KO mice. (D) Relationship between aortic CSE mRNA expression level and levels of plasma lipids. There was a significant negative relationship between CSE mRNA expression and levels of total cholesterol and LDL/VLDL cholesterol. However, its relationship with triglyceride was not statistically significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232559&req=5

pone-0113038-g004: Anti-atherogenic effect of CSE gene activation with higher H2S production.(A) Plasma total cholesterol (n = 8 to 10), (B) LDL/VLDL cholesterol (n = 8 to 10) and (C) triglyceride level (n = 6) were significantly reduced in Tg/KO mice after feeding with 12 weeks of normal diet or atherogenic diet when comparing to KO mice. (D) Relationship between aortic CSE mRNA expression level and levels of plasma lipids. There was a significant negative relationship between CSE mRNA expression and levels of total cholesterol and LDL/VLDL cholesterol. However, its relationship with triglyceride was not statistically significant.
Mentions: During the 12 weeks of diet treatment, both KO and Tg/KO mice increased in their body weight. But their weight gain was significantly reduced once the diets switched from normal to atherogenic at 4 weeks of age (Figure 3A). When comparing Tg/KO mice with KO mice with the same diet, the average weight gain by Tg/KO mice was significant less by about 3 grams (Figure 3A). To demonstrate whether caloric restriction Tg/KO mice could account for cardioprotective effect, food consumption by KO and Tg/KO mice was measured (Table S2). Both KO and Tg/KO mice consumed less in atherogenic diet (Figure 3B). Moreover, the two groups did not differ in the amount of food intake (Figure 3B). Since KO mice shows hypertension in comparison with WT mice groups, it was suspected that overexpression of CSE may lower blood pressure or even cause hypotension in Tg/KO mice. As shown in Figure 3C, CSE gene activation did not significantly change the blood pressure of Tg/KO mice fed with either normal or atherogenic diets. CSE does not appear to affect blood pressure in these mice. Instead, blood pressure seemed to be affected by the level of cholesterol. As shown in Figure 4A, although the total cholesterol of Tg/KO mice was reduced when compared to the KO mice, it was not as low as that of the WT mice.

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