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ACTIVATION OF NUCLEAR RECEPTORS REGULATES ANITI THROMBOTIC ENVIRONMENT ON THE VASCULAR WALL

核受体的激活调节血管壁上的 ANITI 血栓环境

基本信息

批准号：
14572067
负责人：
HORIE Shuichi
金额：
$ 2.18万
依托单位：
Teikyo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Tissue factor (TF), a transmembrane glycoprotein, appeared to be a critical determinant of atherosclerotic plaque thrombogenicity that is important for triggering acute coronary syndromes. We demonstrated that pretreatment of human umbilical vein endothelial cells with ligands for peroxisome-proliferator activating receptor-a (PPARα), such as bezafibrate and Wy14643, greatly diminished the tumor necrosis factor-α (TNFα)-induced enhancement of TF activity in the cells. Such an effect was not observed in cells pretreated with ligands for PPARγ. Promoter assay using a reporter plasmid containing the AP-1 consensus sequence of TF showed that the reduction of TF expression by bezafibrate or Wy14643 is associated with a decrease in the sequence-dependent transcriptional activation. On electrophoretic mobility shift assay, bezafibrate and Wy14643 decreased the interaction between Jun/Fos heterodimer and the AP-1 elementary sequence, and this phenomenon was ascribed not only to a decrease in the levels of Jun/Fos-related nuclear proteins, but also to an increase in formation of RAR/JunB heterodimer that results from the decrease in RAR/RXR heterodimer formation in the cells. A transient expression study showed that coexpression of RXRα and PPARα in the cells decreased the AP-1-dependent promoter activity of TF. These results suggest that ligands for PPARa may serve as repressors of TF-dependent thrombosis of human endothelial cells under various inflammatory conditions through alteration of the heterodimeric partners of nuclear receptor proteins. In the present study, on the other hand, we also found that statins regulate thrombomodulin (TM) expression via inhibition of small G proteins of Rho family; Rac/Cdc42. A statinmediated increase in TM expression by endothelial cells may contribute the beneficial effects of statins on endothelial function.

组织因子（TF），一种跨膜糖蛋白，似乎是动脉粥样硬化斑块血栓形成的一个关键决定因素，是触发急性冠状动脉综合征的重要因素。我们证明，用过氧化物酶体增殖物激活受体α（PPARα）的配体（如苯扎贝特和Wy 14643）预处理人脐静脉内皮细胞，可大大降低肿瘤坏死因子α（TNFα）诱导的TF活性增强。在用PPARγ配体预处理的细胞中未观察到这种效应。启动子分析使用的报告质粒含有AP-1的TF的共识序列表明，TF表达的减少苯扎贝特或Wy 14643与减少序列依赖性转录激活。在电泳迁移率变动分析中，苯扎贝特和Wy 14643降低了Jun/Fos异二聚体与AP-1基本序列之间的相互作用，这一现象不仅归因于Jun/Fos相关核蛋白水平的降低，而且归因于RAR/RXR异二聚体形成的减少导致RAR/JunB异二聚体形成的增加。瞬时表达研究表明，RXRα和PPARα在细胞中的共表达降低了TF的AP-1依赖性启动子活性。这些结果表明，PPARa的配体可以作为TF依赖性血栓形成的人内皮细胞在各种炎症条件下，通过改变核受体蛋白的异二聚体的合作伙伴的阻遏物。在本研究中，另一方面，我们还发现他汀类药物通过抑制Rho家族的小G蛋白Rac/Cdc 42来调节血栓调节蛋白（TM）的表达。他汀类药物介导的内皮细胞TM表达增加可能有助于他汀类药物对内皮功能的有益作用。