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研究生:侯思伃
研究生(外文):Ssu-Yu Hou
論文名稱:Simvastatin抑制血小板凝集作用之機轉探討
論文名稱(外文):Mechanisms involved in the antiplatelet activity of simvastatin
指導教授:許準榕
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:84
中文關鍵詞:血小板凝集降血脂
外文關鍵詞:simvastatinplatelet aggregationphospholipase Cp38 MAPKVASPhydroxyl radicalESR
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Simvastatin是一種HMG CoA還原酶抑制劑。可以降低血漿中膽固醇的含量,在臨床上用於治療高脂血症。最近的研究報告指出simvastatin可以減緩動脈硬化的發展、修飾內皮細胞的功能、穩定plague、增加fibrinolysis、抗發炎和抗血栓等作用。然而simvastatin在血小板上的功用尚未被明確探討,因此我們有意探討在血小板活化過程中,對於訊息傳遞方面的抑制機轉。由本研究結果顯示,simvastatin隨著濃度的增加(20-100 μM),能有效地抑制collagen (1 μg/ml)所引起的人類血小板凝集反應以及ATP釋放反應;且simvastatin (30與50 μM)可以抑制由collagen所刺激細胞內鈣離子的流動、PLCγ2的磷酸化和thromboxane A2的形成。血小板內47 kDa蛋白質磷酸化,這是一個標記protein kinase C活性的方法。在本實驗中我們分別使用 collagen (1 μg/ml)和PDBu (150 nM)促進血小板47 kDa蛋白質磷酸化,發現simvastatin只能抑制由collagen所活化47 kDa蛋白質磷酸化。再者,simvastatin (30和50 μM)亦可抑制由collagen (10 μg/ml)所引起 p38 MAPK的磷酸化反應。此外,simvastatin (30與50 μM)會增加細胞內NO的含量及vasodilator-stimulated phosphoprotein (VASP)的磷酸化。
由上述結果證實,simvastatin抑制血小板活性的作用可能涉及下列路徑:(一) simvastatin可能會調節PLCγ2-PKC-p38MAPK-PLA2-TxA2路徑,而進一步抑制鈣離子的流動。 (二) Simvastatin可能會藉由影響NO/cyclic GMP和cyclic AMP的含量,進而誘發VASP磷酸化;至於為何會增加cyclic GMP和cyclic AMP的作用機轉,我們將會進一步探討。
Simvastatin is a specific inhibitor of 3 hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. It is capable of lowering plasma cholesterol and has successfully used in the clinical treatment of hypercholesterolemia. Recent studies have shown that the effects of simvastatin include the reduction of atherosclerosis morbidity, modification of endothelial function, plaque stability, enhancement of fibrynolysis, anti-inflammatory properties, and anti-thrombosis. However, the mechanisms involved in anti-platelet activity of simvastatin are still unclear, and we are interested in investigating the effects on cellular signal transduction during the process of platelet activation. In this study, simvastatin concentration-dependently (20-100 μM) inhibited collagen (1 μg/ml)-induced human platelet aggregation and ATP release. Simvastatin (30 and 50 μM) inhibited intracellular Ca2+ mobilization, PLCγ2 activity, and thromboxane A2 formation stimulated by collagen (1 μg/ml) in human platelets. Phosphorylation of 47 kDa proteins is a marker of protein kinase C activation, and can be triggered by collagen (1 μg/ml) and PDBu (150 nM). In our experiments, we found that simvastatin (30 and 50 μM) significantly inhibited 47 kDa proteins phosphorylation stimulated by collagen (1 μg/ml) but not PDBu (150nM). In addition, simvastatin (30 and 50 μM) reduced p38 MAPK phosphorylation stimulated by collagen (10 μg/ml) in human platelets. Simvastatin (30 and 50 μM) increased the levels of nitrate and induced phosphorylation of vasodilator-stimulated phosphoprotein (VASP). In conclusion, our study suggested that the mechanisms of simvastatin (30 and 50 μM) in anti-platelet activity maybe involved in the following: (1) simvastatin regulated the activity of PLCγ2-PKC-p38 MAPK-TxA2-Ca2+ pathway. (2) On the other hand, simvastatin may also involve in increasing of NO/cyclic GMP and cyclic AMP, followed by triggered VASP phosphorylation, and finally inhibited platelet aggregation.
中文摘要…………………………………………3
英文摘要…………………………………………5
縮寫表……………………………………………7
一.緒論…………………………………………10
1-1研究背景……………………………………10
1-2研究動機及目的……………………………22
1-3研究範圍……………………………………23
二.實驗材料與方法……………………………24
2-1實驗材料……………………………………24
2-2實驗方法……………………………………28
2-3數據分析……………………………………38
三.結果…………………………………………39
四.討論…………………………………………46
五.結論…………………………………………52
表……………………………………………….53
圖……………………………………………….55
參考文獻……………………………………….71
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