Suppression of pro-inflammatory adhesion molecules by PPAR-delta in human vascular endothelial cells.

Abstract

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.

METHODS AND 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.

• Authors: Yanbo Fan, Ying Wang, Zhihui Tang, Hong Zhang, Xiaomei Qin, Yi Zhu, Youfei Guan, Xian Wang, Bart Staels, Shu Chien, Nanping Wang
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 28 Issue 2 Pg. 315-21 (Feb 2008) ISSN: 1524-4636 [Electronic] United States
• PMID: 18048767 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GW 501516
• Ligands
• PPAR delta
• SOD1 protein, human
• Thiazoles
• (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
• Thioredoxins
• Catalase
• Superoxide Dismutase
• Superoxide Dismutase-1

Topics

• Catalase (metabolism)
• Cells, Cultured
• Endothelial Cells (immunology)
• Humans
• Inflammation (immunology)
• Ligands
• PPAR delta (antagonists & inhibitors, immunology, metabolism)
• Superoxide Dismutase (metabolism)
• Superoxide Dismutase-1
• Thiazoles (pharmacology)
• Thioredoxins (metabolism)
• Umbilical Veins (cytology)
• Up-Regulation