In:
Journal of Vascular Research, S. Karger AG, Vol. 42, No. 6 ( 2005), p. 509-516
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-δ 〈 sup 〉 12,14 〈 /sup 〉 -prostaglandin J2 (15d-PGJ2) and synthetic thiazolidinediones. Recently, a new structural class of potent PPAR-γ agonists, 1,1-bis(3′-indolyl)-1-( 〈 i 〉 p 〈 /i 〉 -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-( 〈 i 〉 p- 〈 /i 〉 t-butylphenyl)methane (DIM-C-pPhtBu) and 1,1-bis(3′-indolyl)-1-( 〈 i 〉 p- 〈 /i 〉 biphenyl)methane (DIM-C-pPhC 〈 sub 〉 6 〈 /sub 〉 H 〈 sub 〉 5 〈 /sub 〉 ), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC 〈 sub 〉 6 〈 /sub 〉 H 〈 sub 〉 5 〈 /sub 〉 , 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 µ 〈 i 〉 M 〈 /i 〉 , DIM-C-pPhtBu and DIM-C-pPhC 〈 sub 〉 6 〈 /sub 〉 H 〈 sub 〉 5 〈 /sub 〉 decreased ICAM-1 expression by 77.5 and 71.3%, respectively, and comparable inhibition (84.4%) was observed for 10 µ 〈 i 〉 M 〈 /i 〉 15d-PGJ2 (p 〈 0.05). In contrast, 10 µ 〈 i 〉 M 〈 /i 〉 ciglitazone and DIM-C-pPhCH 〈 sub 〉 3 〈 /sub 〉 , 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-pPhCH 〈 sub 〉 3 〈 /sub 〉 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-α-activated ECs at lower concentrations than other synthetic PPAR-γ agonists, suggesting the potential clinical utility of 1,1-bis(3′-indolyl)-1-( 〈 i 〉 p- 〈 /i 〉 substituted phenyl) methanes for decreasing endothelial inflammation.
Type of Medium:
Online Resource
ISSN:
1018-1172
,
1423-0135
Language:
English
Publisher:
S. Karger AG
Publication Date:
2005
detail.hit.zdb_id:
1482726-8
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