This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 28/2/315    most recent ATVBAHA.107.149815v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Fan, Y. Articles by Wang, N. PubMed PubMed Citation Articles by Fan, Y. Articles by Wang, N.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:315.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Suppression of Pro-inflammatory Adhesion Molecules by PPAR- in Human Vascular Endothelial Cells

Yanbo Fan; Ying Wang; Zhihui Tang; Hong Zhang; Xiaomei Qin; Yi Zhu; Youfei Guan; Xian Wang; Bart Staels; Shu Chien; Nanping Wang

From the Institute of Cardiovascular Science and Key Laboratory of Molecular Cardiovascular Science (Y.F., Y.W., Z.T., H.Z., X.Q., Y.Z., Y.G., X.W., N.W.), Peking University, Beijing, China; the Diabetes Center (Y.F., Y.W., Z.T., H.Z., X.Q., Y.Z. Y.G., X.W., N.W.), Peking University, Beijing, China; Institut Pasteur de Lille (B.S.) INSERM U545; Université de Lille 2, Faculté de Pharmacie et Faculté de Médecine, Lille, France; and the Departments of Bioengineering and Medicine (S.C.), University of California San Diego, La Jolla, Calif.

Correspondence to Nanping Wang, Institute of Cardiovascular Science, Peking University Health Science Center, Beijing 100083, China. E-mail npwang{at}bjmu.edu.cn

Abstract

Objective— Endothelial activation is implicated in atherogenesis and diabetes. The role of peroxisome proliferator-activated receptor- (PPAR-) in endothelial activation remains poorly understood. In this study, we investigated the anti-inflammatory effect of PPAR- and the mechanism involved.

Methods and Results— In human umbilical vein endothelial cells (HUVECs), the synthetic PPAR- ligands GW0742 and GW501516 significantly inhibited tumor necrosis factor (TNF)-–induced expression of vascular cell adhesion molecule-1 and E-selectin (assayed by real-time RT-PCR and Northern blotting), as well as the ensuing endothelial-leukocyte adhesion. Activation of PPAR- upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. Chromatin immunoprecipitation assays showed that GW0742 switched the association of BCL-6, a transcription repressor, from PPAR- to the vascular cell adhesion molecule (VCAM)-1 promoter. Small interfering RNA reduced endogenous PPAR- expression but potentiated the suppressive effect of GW0742 on EC activation, which suggests that the nonliganded PPAR- may have an opposite effect.

Conclusions— We have demonstrated that ligand activation of PPAR- in ECs has a potent antiinflammatory effect, probably via a binary mechanism involving the induction of antioxidative genes and the release of nuclear corepressors. PPAR- agonists may have a potential for treating inflammatory diseases such as atherosclerosis and diabetes.

By using the selective agonists and siRNA-mediated gene silencing, we have demonstrated that ligand-activation of PPAR- in primary-cultured human endothelial cells has a potent antiinflammatory effect via a novel binary mechanism involving the induction of antioxidative genes and the release of nuclear corepressors.

Key Words: adhesion molecules • nuclear receptor • endothelium • gene expression • reactive oxygen species