Calabrò Paolo, Samudio Ismael, Safe Stephen H, Willerson James T, Yeh Edward T H
Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas-Houston Health Science Center, Houston, Tex., USA.
J Vasc Res. 2005 Nov-Dec;42(6):509-16. doi: 10.1159/000088260. Epub 2005 Sep 9.
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-gamma (PPAR-gamma) ligands, including 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and synthetic thiazolidinediones. Recently, a new structural class of potent PPAR-gamma 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-gamma-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-pPhC(6)H(5)), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC(6)H(5), DIM-C- pPhtBu, or 15d-PGJ2 decreased tumor necrosis factor-alpha (TNF-alpha)-induced intercellular adhesion molecule (ICAM)-1 expression in a concentration-dependent manner. At a concentration of 10 microM, DIM-C-pPhtBu and DIM-C-pPhC(6)H(5) decreased ICAM-1 expression by 77.5 and 71.3%, respectively, and comparable inhibition (84.4%) was observed for 10 microM 15d-PGJ2 (p < 0.05). In contrast, 10 microM ciglitazone and DIM-C-pPhCH(3), which exhibits low PPAR-gamma agonist activity, were inactive. The two new PPAR-gamma agonists and 15d-PGJ2 also inhibited TNF-alpha-induced interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production in supernatants of TNF-alpha-stimulated ECs, whereas ciglitazone and DIM-C-pPhCH(3) did not decrease TNF-alpha-induced expression of these two proteins. This new structural class of PPAR-gamma agonists inhibited the expression of ICAM-1 and the production of IL-6 and MCP-1 in TNF-alpha-activated ECs at lower concentrations than other synthetic PPAR-gamma agonists, suggesting the potential clinical utility of 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes for decreasing endothelial inflammation.
内皮细胞（ECs）表达的促炎细胞因子和黏附分子在动脉粥样硬化的起始和发展过程中起着关键作用。能够对抗血管细胞中这些炎症效应的物质包括过氧化物酶体增殖物激活受体γ（PPAR-γ）配体，如15-脱氧-Δ¹²,¹⁴-前列腺素J2（15d-PGJ2）和合成噻唑烷二酮类药物。最近，一种新型强效PPAR-γ激动剂——1,1-双（3'-吲哚基）-1-（对-取代苯基）甲烷已被鉴定出来。本研究的目的是评估该类中的两种具有PPAR-γ活性的成员，即1,1-双（3'-吲哚基）-1-（对-叔丁基苯基）甲烷（DIM-C-pPhtBu）和1,1-双（3'-吲哚基）-1-（对-联苯基）甲烷（DIM-C-pPhC₆H₅）在体外对内皮细胞的抗炎作用。用DIM-C-pPhC₆H₅、DIM-C-pPhtBu或15d-PGJ2预处理内皮细胞，可呈浓度依赖性地降低肿瘤坏死因子-α（TNF-α）诱导的细胞间黏附分子（ICAM）-1的表达。在10微摩尔浓度时，DIM-C-pPhtBu和DIM-C-pPhC₆H₅分别使ICAM-1表达降低77.5%和71.3%，而10微摩尔的15d-PGJ2则产生了相当的抑制作用（84.4%）（p<0.05）。相比之下，10微摩尔的吡格列酮和具有低PPAR-γ激动剂活性的DIM-C-pPhCH₃则无活性。这两种新型PPAR-γ激动剂和15d-PGJ2还抑制了TNF-α刺激的内皮细胞上清液中TNF-α诱导的白细胞介素-6（IL-6）和单核细胞趋化蛋白-1（MCP-1）的产生，而吡格列酮和DIM-C-pPhCH₃并未降低TNF-α诱导的这两种蛋白的表达。与其他合成PPAR-γ激动剂相比，这种新型结构的PPAR-γ激动剂在较低浓度下就能抑制TNF-α激活的内皮细胞中ICAM-1的表达以及IL-6和MCP-1的产生，这表明1,1-双（3'-吲哚基）-1-（对-取代苯基）甲烷在减轻内皮炎症方面具有潜在的临床应用价值。
