2001 Fiscal Year Final Research Report Summary
Increase in antithrombotic function vascular endothelium antithrombin-III
| Project/Area Number |
11838017
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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 Institution | Showa Pharmaceutical University |
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Principal Investigator |
ISHII Hidemi Showa Pharmaceutical Universit, Department of Public Health, Professor, 薬学部, 教授 (50102710)
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| Project Period (FY) |
1999 – 2001
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| Keywords | endothelial cells / antithrombin-III / tissue factor / ELAM-1 / thrombomododulin / bleomycin / oxidized LDL / NF-KB |
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| Research Abstract |
Normal vascular endothelial cells preferentially produce antithrombotic factors such as prostaglandin 12 and thrombomodulin than preduction of prothrombotic factors such as tissue factor, so that the cells are preventing thrombus formation. However, if the cells are stimulated by various agonists in the blood, the cells change balance to reduce production of antithrombomotic factors and increase production of prothrombotic factor, so that the blood was turned to form thrombus. Antithrombin-III(AF-III), which is a physiological inhibitor for thrombin, stimulates endothelial cells and induces production of prostaglandin I2. The present studies were undertaken to evaluate whether AT-III can promote various antithrombotic functions in endothelial cells other than the induced production of prostaglandin I2.
1. When cultured vascular endothelial cells were exposed to TNFα, the cells induce tissue factor (TF) expression on the membrane surface of the cells through up-regulation of TF transcription. Pretreatment of the cells with At-III prevented TNFα-induced TF expression through depression of TF gene transcription.
2. Expression of ELAM-1, which is a adhesion molecule for lenkocytes, was induced by exposure of endothelial cells to bleomycin, a anticancer drug, on the cell surface through up-regulation of ELAM-1 transcription. AT-III pretreatment did not prevent the bleomycin-induced ELAM-1 expression.
3. Oxidized phospholipid in oxidized LDL reduced expression of RARs, RXRα and Sp1 proteins in endothelial cells. These reduced proteins induced thrombomodulin(TM) expression on the surface of the cells through suppression of transcription of TM gene. AT-III pretreatment did not prevent oxidized LDL-induced down-regulation of TM. These results suggested that AT-III can act as antithomotic agent through inhibition of thrombin and induction of prostaglandin I2 producion, but not the bleomycin-induced ELAM-1 expression and the oxidized LDL-induced TM down-regulation.
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