他汀类药物作为细胞抗血栓药。

Haemostasis Pub Date : 1999-01-01 DOI:10.1159/000022496
J W Fenton, G X Shen
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引用次数: 31

摘要

在临床试验中,他汀类药物(伐他汀)通过降低胆固醇来减少心血管疾病,但这种关系尚不清楚。我们推断:(1)凝血酶(IIa)是心血管事件的潜在介质,(2)IIa通过其主要受体[蛋白酶激活受体-1 (PAR-1)]介导细胞事件,(3)他汀类药物抑制PAR-1激活和组织因子上调之间的异戊二烯类依赖事件,导致IIa的产生。在类异戊二烯途径中,他汀类药物在胆固醇和其他途径分支分化之前抑制甲羟戊酸合成,后者产生细胞调节物质(如ras蛋白)。通过血小板和其他细胞中的PAR-1, IIa刺激包括ras蛋白在内的g蛋白偶联机制。我们假设他汀类药物在细胞水平上表现出抗血栓特性,下调IIa的产生,他汀类药物可能构成一类新的抗血栓药物。
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Statins as cellular antithrombotics.

In clinical trials, statins (vastatins) reduce cardiovascular disease with cholesterol reduction, but this relationship is unclear. We reasoned that (1) thrombin (IIa) is an underlying mediator of cardiovascular events, (2) IIa mediates cellular events through its primary receptor [protease-activated receptor-1 (PAR-1)], and (3) statins inhibit an isoprenoid-dependent event between PAR-1 activation and tissue factor upregulation leading to IIa generation. In the isoprenoid pathways, statins inhibit mevalonic acid synthesis prior to divergence of the cholesterol and other pathway branches, where the latter produce cell-regulating substances (e.g., ras proteins). Through PAR-1 in platelets and other cells, IIa stimulates G-protein-coupled mechanisms including ras proteins. We hypothesize that statins exhibit antithrombotic properties at the cellular level downregulatating IIa generation and that statins may constitute a novel class of antithrombotics.

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