Inhibition of tumor-necrosis-factor-α induced endothelial cell activation by a new class of PPAR-γ agonists: An in vitro study showing receptor-independent effects

Paolo Calabrò, Ismael Samudio, Stephen H. Safe, James T. Willerson, Edward T.H. Yeh

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Proinflammatory cytokines and adhesion molecules expressed by endothelial cells (ECs) play a critical role in initiating and promoting atherosclerosis. Agents that oppose these inflammatory effects in vascular cells include peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands, including 15-deoxy-δ12,14-prostaglandin J2 (15d-PGJ2) and synthetic thiazolidinediones. Recently, a new structural class of potent PPAR-γ agonists, 1,1-bis(3′-indolyl)-1-(p-substituted phenyl) methanes, has been characterized. The purpose of this study was to evaluate the anti-inflammatory effects of two PPAR-γ-active members of this class, 1,1-bis(3′-indolyl)-1-(p-t-butylphenyl)-methane (DIM-C-pPhtBu) and 1,1-bis(3′-indolyl)-1-(p-biphenyl)methane (DIM-C-pPhC6H 5), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC 6H5, DIM-C-pPhtBu, or 15d-PGJ2 decreased tumor necrosis factor-α (TNF-α)-induced intercellular adhesion molecule (ICAM)-1 expression in a concentration-dependent manner. At a concentration of 10 μM, DIM-C-pPhtBu and DIM-C-PPhC6H5 decreased ICAM-1 expression by 77.5 and 71.3%, respectively, and comparable inhibition (84.4%) was observed for 10 μM 15d-PGJ2 (p < 0.05). In contrast, 10 μM ciglitazone and DIM-C-pPhCH3, which exhibits low PPAR-γ agonist activity, were inactive. The two new PPAR-γ agonists and 15d-PGJ2 also inhibited TNF-α-induced interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production in supernatants of TNF-α-stimulated ECs, whereas ciglitazone and DIM-C-pPhCH3 did not decrease TNF-α-induced expression of these two proteins. This new structural class of PPAR-γ agonists inhibited the expression of ICAM-1 and the production of IL-6 and MCP-1 in TNF-γ-activated ECs at lower concentrations than other synthetic PPAR-γ agonists, suggesting the potential clinical utility of 1,1-bis(3′-indolyl)-1-(p-substituted phenyl) methanes for decreasing endothelial inflammation.

Original languageEnglish (US)
Pages (from-to)509-516
Number of pages8
JournalJournal of Vascular Research
Volume42
Issue number6
DOIs
StatePublished - Nov 2005
Externally publishedYes

Keywords

  • Adhesion molecules
  • Atherosclerosis
  • Endothelial cells
  • Inflammation
  • PPAR-γ

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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