Suppression of pro-inflammatory adhesion molecules by PPAR-δ 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

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

OBJECTIVE - Endothelial activation is implicated in atherogenesis and diabetes. The role of peroxisome proliferator-activated receptor-δ (PPAR-δ) in endothelial activation remains poorly understood. In this study, we investigated the anti-inflammatory effect of PPAR-δ and the mechanism involved. METHODS AND RESULTS - In human umbilical vein endothelial cells (HUVECs), the synthetic PPAR-δ ligands GW0742 and GW501516 significantly inhibited tumor necrosis factor (TNF)-α-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-δ 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-δ to the vascular cell adhesion molecule (VCAM)-1 promoter. Small interfering RNA reduced endogenous PPAR-δ expression but potentiated the suppressive effect of GW0742 on EC activation, which suggests that the nonliganded PPAR-δ may have an opposite effect. CONCLUSIONS - We have demonstrated that ligand activation of PPAR-δ 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-δ agonists may have a potential for treating inflammatory diseases such as atherosclerosis and diabetes.

Original languageEnglish (US)
Pages (from-to)315-321
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume28
Issue number2
DOIs
StatePublished - Feb 2008

Keywords

  • Adhesion molecules
  • Endothelium
  • Gene expression
  • Nuclear receptor
  • Reactive oxygen species

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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