| Project/Area Number |
14572067
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Teikyo University |
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Principal Investigator |
HORIE Shuichi FAC.PHARM.SCI.,TEIKYO UNIV., DEPT.CLIN.MOL.BIOL, ASSOCIATE PROFESSOR, 薬学部, 助教授 (60157063)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | THROMBOMODULIN / TISSUE FACTOR / ENDOTHELIAL CELLS / ANTITHROMBOTICACTION / NUCLEAR RECEPTOR / RETINOIC ACID / AP-1 / SP1 / Sp1 / 腫瘍壊死因子 / フィブレート系薬剤 / スタチン系薬剤 |
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| Research Abstract |
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.
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