Pitavastatin-induced Thrombomodulin expression by endothelial cells acts via inhibition of small G proteins of the Rho family
Pitavastatin-induced Thrombomodulin expression by endothelial cells acts via inhibition of small G proteins of the Rho family
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DOI：
10.1161/01.atv.0000060461.64771.f0
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发表时间：
2003-03-01
影响因子：
8.7
通讯作者：
Miyamori, I
中科院分区：
文献类型：
--
作者：
Masamura, K;Oida, K;Miyamori, I
目的：3-羟基-3-甲基辅酶A还原酶抑制剂（他汀类药物）能够以独立于其降脂活性的方式保护血管系统。内皮细胞抗血栓形成特性的主要特征是血栓调节蛋白（TM）表达的增加而不诱导组织因子（TF）表达。我们研究了他汀类药物对TM和TF的表达内皮cells.Methods和Results-The孵育的内皮细胞与匹伐他汀导致浓度和时间依赖性增加细胞TM抗原和mRNA水平的影响。相反，在相同条件下，TF mRNA的表达没有被诱导。一项核连续研究表明，匹伐他汀加速TM转录速率。甲羟戊酸或香叶基香叶基焦磷酸阻止匹伐他汀刺激TM表达。牛儿基牛儿基转移酶-I和Rac/Cdc 42的GGTI-286和梭菌Sordellii致死毒素的特异性抑制，分别增强TM的表达，而肉毒梭菌C3外切酶的Rho灭活是无效的。结论他汀类药物调节TM的表达通过抑制小G蛋白的Rho家族; Rac/Cdc 42。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。
Objective-3-Hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. The main feature of the antithrombotic properties of endothelial cells is an increase in the expression of thrombomodulin (TM) without induction of tissue factor (TF) expression. We investigated the effect of statins on the expression of TM and TF by endothelial cells.Methods and Results-The incubation of endothelial cells with pitavastatin led to a concentration-and time-dependent increase in cellular TM antigen and mRNA levels. In contrast, the expression of TF mRNA was not induced under the same conditions. A nuclear run-on study revealed that pitavastatin accelerates TM transcription rate. The stimulation of TM expression by pitavastatin was prevented by either mevalonate or geranylgeranylpyrophosphate. Specific inhibition of geranylgeranyltransferase-I and Rac/Cdc42 by GGTI-286 and Clostridium sordellii lethal toxin, respectively, enhanced TM expression, whereas inactivation of Rho by Clostridium botulinum C3 exoenzyme was ineffective.Conclusions-Statins regulate TM expression via inhibition of small G proteins of the Rho family; Rac/Cdc42. A statin-mediated increase in TM expression by endothelial cells may contribute to the beneficial effects of statins on endothelial function.