臺灣博碩士論文加值系統

最近大量的臨床研究試驗已經證實statins，三氫氧基三甲基穀胱胺基輔酶還原酶的抑制劑，其用於初級和次級的預防心血管疾病時顯著的降低病患的罹患率及死亡率，不但藉由其能使脂肪降低的能力並且也藉由和非脂肪相關的機轉。過去研究報告出statins藥物能夠拮抗由腫瘤壞死因子所抑制的血栓調節蛋白（thrombomodulin, TM）表現，而TM於抗凝血與抗發炎機轉中扮演一個相當重要的角色。在本實驗中我們發現（1）腫瘤壞死因子會刺激黏附分子的表現，但若先處理pravastatin及simvastatin無法使被腫瘤壞死因子刺激的黏附分子的表現有減少的情形;而腫瘤壞死因子也會刺激CD40的表現，但若先處理pravastatin及simvastatin則可使被腫瘤壞死因子所刺激的CD40表現減少。（2）使用pravastatin及simvastatin處理細胞24小時後，可以觀察到內皮細胞表現的TM量顯著增加。（3）腫瘤壞死因子會抑制TM的表現，但若先處理過pravastatin及simvastatin則可使被腫瘤壞死因子所抑制的TM表現增加。（4）腫瘤壞死因子會活化MAPK磷酸化，但先處理過pravastatin及simvastatin則可以使被腫瘤壞死因子所活化的MAPK磷酸化下降; 而使用MAPK的抑制劑卻無法增加被腫瘤壞死因子抑制的TM表現。另外，腫瘤壞死因子會抑制TM的表現，但先處理10μM的GGTI-286及1 ng/ml的Tcd-B則可使被腫瘤壞死因子抑制的TM表現增加; 但若使用10μM的Y-27632及10μM C3先處理後卻無法使被腫瘤壞死因子所抑制的TM表現增加。進一步，腫瘤壞死因子會活化NF-κB，但若先處理pravastatin及simvastatin則可使被腫瘤壞死因子所活化的NF-κB活性下降。由這些結果顯示statins藥物調控被腫瘤壞死因子抑制的TM表現增加可能是經由抑制小分子G蛋白（small G-protein），再進而影響轉錄因子NF-κB的活化路徑所調控的，而並不經由MAPK訊息傳導路徑。由以上結論得知人類主動脈內皮細胞對statins處理所造成TM表現增加，可以用來解釋這些常用的statins具有多樣性的作用機轉，而有異於膽固醇所產生的作用機制。

Recent large clinical trials have demonstrated that statin（HMG-CoA reductase inhibitor）, markedly reduces morbidity and mortality when used in the primary and secondary prevention of cardiovascular diseases not only by its lipid-lowering potential but also by its nonlipid-related mechanism. It has been reported that statins can counteract TNF-alpha induced downregulation of thrombomodulin（TM）, which plays a critical role in both anticoagulation and anti-inflammation. In this study, Human Aortic Endothelial Cells（HAECs） pretreated with these two different statins, pravastatin and simvastatin, were used to exmine the expression of adhesion molecules, CD40, TM under TNF-alpha induction and their underlying mechanism. We found that pretreatment with these two statins in TNF-alpha -treated HAECs（1） decreased the expression of CD40 but did not affect the expression of ICAM-1 and VCAM-1.（2）increased the expression of TM.（3）Pretreatment of these two statins increased the expression of TM.（4）Pretreatment of these two statins in TNF-alpha -treated HAECs decreased the activation of MAPK, whereas pretreatment of MAPK inhibitirs in TNF-alpha –treated HAECs did not affect the expression of TM. Futhermore, pretreatment with GGTI-286 and Tcd-B in TNF-alpha –treated HAECs increased the expression of TM, in contrast pretreatment with Y-27632 and C3 did not affect the expression of TM, in addition, pretreatment with these two statins in TNF-alpha –treated HAECs decreased the activation of NF-κB. From the alone results, the effects of statins on TM expression may be mediated by the inactivation of Rac1 and Cdc42 than by the inactivation of NF-κB but not though MAPKs pathway. The increase in endothelial cell TM activity in response to statin constitutes a novel pleiotropic（non-lipid-related） effect of these commonly used compounds.

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