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Cardiovascular Research Advance Access [Accepted Manuscript] published online on August 9, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn224
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Endothelium-specific Overexpression of Class III Deacetylase SIRT1 Decreases Atherosclerosis in Apolipoprotein E–Deficient Mice

Qing-jun Zhanga,c,d, Zhao Wanga,c, Hou-zao Chena,c, Shuang Zhoua, Wei Zhenga, Guang Liua, Yu-sheng Weia, Hua Caib, De-pei Liua,* and Chih-chuan Lianga

a 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, P. R. China
b Division of Molecular Medicine, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, University of California Los Angeles (UCLA), Los Angeles, CA, USA

* Corresponding author. Tel: +8610-65296415; Fax: +8610-65105093 Email: liudp{at}pumc.edu.cn

Aims: 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.

Methods: Human umbilical vein endothelial cells (HUVECs) were used to study effects of oxidized LDL on SIRT1 expression. Endothelial cell-specific SIRT1 transgenic (SIRT1-Tg) mice were used to study the effect of SIRT1 on aortic vascular tone. SIRT1-Tg mice were crossed with apolipoprotein E null (apoE–/-) mice to obtain SIRT1-Tg/apoE–/- mice for analysis of atherogenesis in the presence of endothelial overexpression of SIRT1.

Results: SIRT1 expression in HUVECs was increased by treatment with oxidative LDL. Adenoviral-mediated overexpression of SIRT1 was protective of apoptosis of HUVECs. Calorie restriction increased, whereas high-fat diet decreased, SIRT1 expression in mouse aortas. In endothelial cell-specific SIRT1 transgenic (SIRT1-Tg) mice, high fat-induced impairment in endothelium-dependent vasorelaxation was improved compared to 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 to 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.

Time for primary review: 38 Days

c these authors contribute equally to this work.

d Current address: Department of internal Medicine-Cardiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235, USA


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