Anti-atherogenic effect of hydrogen sulfide by over-expression of cystathionine gamma-lyase (CSE) gene.
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.
Department of Surgery, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.
Sau Ha
SH
Cheung
Department of Surgery, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.
Wai Kei
WK
Kwok
Department of Anatomical and Cellular Pathology, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.
Ka Fai
KF
To
Department of Surgery, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.
James Yun Wong
JY
Lau
D052242:Adiponectin / Q000097:blood; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology; D001794:Blood Pressure; D001835:Body Weight; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005979:Glutathione Peroxidase / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic / Q000503:physiopathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D052242:Adiponectin; D001057:Apolipoproteins E; D020738:Leptin; D008055:Lipids; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D005979:Glutathione Peroxidase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide