权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Increase in antithrombotic function vascular endothelium antithrombin-III

抗血栓功能增加血管内皮抗凝血酶-III

基本信息

批准号：
11838017
负责人：
ISHII Hidemi
金额：
$ 2.24万
依托单位：
Showa Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11838017/
关键词：
endothelial cells antithrombin-III tissue factor ELAM-1 thrombomododulin bleomycin oxidized LDL NF-KB 酸化リン脂質レチノイン酸 Sp1 RAR RXR 血管内皮細胞炎症性サイトカインアンチトロンビンIII ELAM 組織因子mRNA

项目摘要

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.

正常血管内皮细胞优先产生抗血栓因子如前列腺素12和凝血调节素，而不产生促血栓因子如组织因子，因此细胞阻止血栓形成。然而，如果细胞受到血液中各种激动剂的刺激，细胞就会改变平衡，减少抗血栓因子的产生，增加血栓形成因子的产生，从而使血液转向形成血栓。抗凝血素- iii （AF-III）是一种凝血酶的生理性抑制剂，刺激内皮细胞，诱导前列腺素I2的产生。目前的研究是为了评估AT-III是否可以促进内皮细胞的各种抗血栓功能，而不是诱导前列腺素I2.1的产生。当培养的血管内皮细胞暴露于TNFα时，细胞通过上调TF转录诱导细胞膜表面组织因子（tissue factor， TF）的表达。At-III预处理细胞通过抑制TF基因转录抑制tnf α诱导的TF表达。内皮细胞暴露于抗癌药物博来霉素后，通过上调ELAM-1的转录，诱导内皮细胞表面表达ELAM-1，这是一种内皮细胞的粘附分子。AT-III预处理未阻止博莱霉素诱导的ELAM-1表达。氧化LDL中的氧化磷脂可降低内皮细胞中RARs、RXRα和Sp1蛋白的表达。这些减少的蛋白通过抑制凝血调节蛋白基因的转录诱导凝血调节蛋白在细胞表面的表达。AT-III预处理不能阻止氧化ldl诱导的TM下调。这些结果表明，AT-III可以通过抑制凝血酶和诱导前列腺素I2的产生而发挥抗肿瘤作用，但不能通过抑制博莱霉素诱导的ELAM-1表达和氧化ldl诱导的TM下调来发挥抗肿瘤作用。