Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice.
OBJECTIVE
Hazardous environmental and genetic factors can damage endothelial cells to induce atherosclerotic vascular disease. Recent studies suggest that class III deacetylase SIRT1 may promote cell survival via novel antioxidative mechanisms. The current study tested the hypothesis that SIRT1, specifically overexpressed in the endothelium, is atheroprotective.


RESULTS
Human umbilical vein endothelial cells (HUVECs) were used to study the effects of oxidized low-density lipoprotein (LDL) on SIRT1 expression. Endothelial cell-specific SIRT1 transgenic (SIRT1-Tg) mice were used to study the effects of SIRT1 on aortic vascular tone. SIRT1-Tg mice were crossed with apolipoprotein E null (apoE(-/-)) mice to obtain SIRT1-Tg/apoE(-/-) mice for the analysis of atherogenesis in the presence of endothelial overexpression of SIRT1. SIRT1 expression in HUVECs was increased by the treatment with oxidative LDL. Adenoviral-mediated overexpression of SIRT1 was protective of apoptosis of HUVECs. Calorie restriction increased, whereas high-fat diet decreased, the SIRT1 expression in mouse aortas. In SIRT1-Tg mice, high fat-induced impairment in endothelium-dependent vasorelaxation was improved compared with that of wild-type littermates. This was accompanied by an upregualtion of aortic endothelial nitric oxide synthase expression in the SIRT1-Tg mice. The SIRT1-Tg/apoE(-/-) mice had less atherosclerotic lesions compared with apoE(-/-) controls, without affecting blood lipids and glucose levels.


CONCLUSIONS
These results suggest that endothelium-specific SIRT1 overexpression likely suppresses atherogenesis via improving endothelial cell survival and function.
Zhang
Qing-Jun
QJ
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, PR China.
Wang
Zhao
Z
Chen
Hou-Zao
HZ
Zhou
Shuang
S
Zheng
Wei
W
Liu
Guang
G
Wei
Yu-Sheng
YS
Cai
Hua
H
Liu
De-Pei
DP
Liang
Chih-Chuan
CC
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D001786:Blood Glucose / Q000378:metabolism; D031204:Caloric Restriction; D002478:Cells, Cultured; D004041:Dietary Fats; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014664:Vasodilation
D001057:Apolipoproteins E; D001786:Blood Glucose; D004041:Dietary Fats; D008055:Lipids; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins