Kunieda Yasufumi, Nakagawa Katsumi, Nishimura Hiromi, Kato Hisato, Ukimura Naoki, Yano Shingo, Kawano Hidehiko, Kimura Shinzo, Nakagawa Masao, Tsuji Hajime
Second Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Thromb Res. 2003 Jun 1;110(4):227-34. doi: 10.1016/s0049-3848(03)00346-3.
It has been demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) reduce the incidence of acute cardiovascular events in patients with hyperlipidemia. Recent reports have shown that the protective effects of these drugs against cardiovascular events are also observed in patients without hyperlipidemia, but the mechanism of this favorable effect still remains unclear. In this study, the effects of HRIs on the endothelial regulation of thrombus formation were elucidated.
The mRNA and protein expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) induced by angiotensin II (Ang II) were evaluated in cultured rat aortic endothelial cells. Pretreatment with simvastatin (0.03-3 microg/ml) significantly inhibited TF and PAI-1 induction by Ang II in a dose- and time-dependent manner. These inhibitions were significantly attenuated by mevalonic acid or geranylgeranyl pyrophosphate. Both Rho inhibitor, C3 exoenzyme, and Rho kinase inhibitor, Y-27632, mimicked the inhibitory effects of simvastatin against TF and PAI-1 induced by Ang II. This result suggested that the Rho/Rho kinase pathway is related to the TF and PAI-1 induction by Ang II.
It was indicated that simvastatin maintains endothelial cells to be antithrombotic by inhibiting TF and PAI-1 expression via the Rho/Rho kinase pathways in which AngII induces TF and PAI-1 expression. These observations explain, at least partly, the mechanism of the favorable effects of simvastatin in reducing the thrombotic events.
已证实3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂(HRIs)可降低高脂血症患者急性心血管事件的发生率。最近的报告显示,在无高脂血症的患者中也观察到了这些药物对心血管事件的保护作用,但其有利作用的机制仍不清楚。在本研究中,阐明了HRIs对血栓形成的内皮调节作用。
在培养的大鼠主动脉内皮细胞中评估血管紧张素II(Ang II)诱导的组织因子(TF)和纤溶酶原激活物抑制剂-1(PAI-1)的mRNA和蛋白表达。辛伐他汀(0.03 - 3微克/毫升)预处理以剂量和时间依赖性方式显著抑制Ang II诱导的TF和PAI-1表达。甲羟戊酸或香叶基香叶基焦磷酸显著减弱了这些抑制作用。Rho抑制剂C3外切酶和Rho激酶抑制剂Y-27632均模拟了辛伐他汀对Ang II诱导的TF和PAI-1的抑制作用。该结果表明Rho/Rho激酶途径与Ang II诱导的TF和PAI-1表达有关。
表明辛伐他汀通过Rho/Rho激酶途径抑制TF和PAI-1表达,从而维持内皮细胞的抗血栓形成状态,其中AngII诱导TF和PAI-1表达。这些观察结果至少部分解释了辛伐他汀在减少血栓形成事件中有利作用的机制。