Suppression of pro-inflammatory adhesion molecules by PPAR-delta in human vascular endothelial cells.
OBJECTIVE
Endothelial activation is implicated in atherogenesis and diabetes. The role of peroxisome proliferator-activated receptor-delta (PPAR-delta) in endothelial activation remains poorly understood. In this study, we investigated the anti-inflammatory effect of PPAR-delta and the mechanism involved.


RESULTS
In human umbilical vein endothelial cells (HUVECs), the synthetic PPAR-delta ligands GW0742 and GW501516 significantly inhibited tumor necrosis factor (TNF)-alpha-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-delta 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-delta to the vascular cell adhesion molecule (VCAM)-1 promoter. Small interfering RNA reduced endogenous PPAR-delta expression but potentiated the suppressive effect of GW0742 on EC activation, which suggests that the nonliganded PPAR-delta may have an opposite effect.


CONCLUSIONS
We have demonstrated that ligand activation of PPAR-delta 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-delta agonists may have a potential for treating inflammatory diseases such as atherosclerosis and diabetes.
Fan
Yanbo
Y
Institute of Cardiovascular Science and Key Laboratory of Molecular Cardiovascular Science, Peking University Health Science Center, Beijing 100083, China.
Wang
Ying
Y
Tang
Zhihui
Z
Zhang
Hong
H
Qin
Xiaomei
X
Zhu
Yi
Y
Guan
Youfei
Y
Wang
Xian
X
Staels
Bart
B
Chien
Shu
S
Wang
Nanping
N
D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008024:Ligands; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013844:Thiazoles / Q000494:pharmacology; D013879:Thioredoxins / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation; D010636:Phenols; D013438:Sulfhydryl Compounds
D002374:Catalase; D008024:Ligands; D047494:PPAR delta; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013844:Thiazoles; D013879:Thioredoxins; C425931:GW 501516; C000606290:SOD1 protein, human; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds