臺灣博碩士論文加值系統

血管平滑肌細胞的遷移和基質金屬蛋白酶(matrix metalloproteinase ; MMP) 的活化，在動脈粥狀硬化的發展中扮演一個重要的角色。紫檀芪 (Pterostilbene) 是存在葡萄與藍莓中的典型黃酮類化合物，目前許多研究發現，紫檀芪具抗發炎、抗氧化與抗癌的功效。因此，本研究欲探討紫檀芪抑制血管平滑肌細胞遷移與基質金屬蛋白酶的相關性。本研究利用MTT assay來評估紫檀芪對平滑肌細胞株(A7r5)存活率的影響；接著利用migration/invasion assay、wound healing assay 及zymography 來評估紫檀芪對平滑肌細胞株(A7r5)，其細胞移動及基質金屬蛋白酶活性的影響；最後以西方墨點法評估紫檀芪抑制細胞外基質(ECM) 分解酵素的機制分析，如影響侵襲能力的基質金屬蛋白水解酶活性有關的訊息傳遞MAPK family ERK 1/2、p38及JNK 1/2、phosphatidylinositol 3-kinase (PI3K)/Akt pathway。Gelatin zymography與西方墨點法皆顯示紫檀芪會降低MMP-2的分泌與蛋白質表現，而migration/invasion assay與wound healing assay的遷移試驗顯示紫檀芪可有效抑制平滑肌細胞的遷移。另外，在訊息傳遞路徑的影響，可從西方墨點法的結果證實紫檀芪可誘發ERK磷酸化，故再利用ERK抑制劑去觀察其對細胞遷移與MMP-2的影響，結果也顯示紫檀芪是透過ERK的活化來抑制細胞遷移與MMP-2的表現。綜合以上結果可知，紫檀芪可有效抑制血管平滑肌的增生與遷移，以延緩動脈粥狀硬化的病程發展，因此，在臨床上可建議心血管相關疾病之患者可適量補充莓果(藍莓與葡萄)，將有助於預防動脈粥狀硬化。

Smooth muscle cells (SMCs) migration and matrix metalloproteinase-2 (MMP-2) activation are main roles in atherosclerosis. Pterostilbene (trans-3, 5-dimethoxy-4-hydroxystilbene), a flavonoid extensively found in blueberries and grapes, confers potent antioxidant, anti-inflammatory and anticarcinogenic properties. The present study aimed to investigate the anti-atheroscleroic property of pterostilbene in the rat smooth muscle cell (SMC) A7r9 cell lines and the underlying mechanisms. The cytotoxic effect of pterostilbene on smooth muscle cell line (A7r5) was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) assay. The mobility of vascular smooth muscle cells through the extracellular matrix was determined by migration assay and wound healing assay. Evaluate of matrix metalloproteinase (MMP) activation and protein expression by gelatin zymography and western blot. In this study, pterostilbene treatment significantly inhibited migration/invasion capacities of in A7r9 cell. Pterostilbene was also found to significantly decreased MMP-2 activity and expression by gelatin zymography and western blot assay in SMC. In the MAPK signaling pathway, western blot assay also indicated that pterostilbene up-regulated the phosphorylation of extracellular-signal- regulated kinase (Erk) 1/2. Moreover, inhibition of Erk1/2 by specific inhibitors significantly abolished the pterostilbene-decreased expression of MMP-2 and migration/invasion capacities. These findings suggest that pterostilbene inhibited SMC migration and that MMP-2 activation could be mediated via Erk1/2 phosphorylation. It is further possible that pterostilbene could play a novel role in the treatment of atherosclerosis.

封面 I
目次 II
附圖次 VII
圖次 VIII
附表次 X
縮寫表 XI
謝誌 XII
中文摘要 XIII
英文摘要 XV
第一章 緒論 1
第一節 研究背景 1
第二節 研究動機 3
第二章 文獻探討 4
第一節 動脈粥狀硬化 4
一、血管的構造 4
二、動脈粥狀硬化的形成 6
三、基質金屬蛋白酶 9
四、訊息傳遞路徑Mitogen-Activated Protein Kinases (MAPK) 13
五、訊息傳遞路徑Phosphatidylinositol-3-kinase (PI3K) 16
第二節 紫檀芪 17
一、類黃酮之結構與分類 17
二、紫檀芪 20
第三節 研究目的 21
第三章 研究方法 22
第一節 實驗材料與配製方法 22
一、藥品試劑 22
二、實驗設備 24
三、試劑配製 26
四、實驗細胞株 32
第二節 A7r5 細胞培養 (A7r5 cell culture) 33
一、A7r5 細胞解凍 33
二、A7r5 細胞繼代培養 34
三、A7r5 細胞冷凍 35
第三節 紫檀芪(Pterostilbene)之配製 36
第四節 實驗方法 37
一、細胞存活率測試 (Analysis of cell viability) 37
二、傷口癒合試驗 (wound healing assay) 38
三、體外細胞移動性試驗 (Cell mobility assay in vitro) 39
細胞遷移性試驗 (Cell migration assay) 39
細胞侵入性試驗 (Cell invasion assay) 40
四、受質十二烷基硫酸鈉聚丙醯胺膠體電泳 (Substrate SDS-PAGE) 42
細胞培養液收集 (cell culture medium collection ) 42
明膠蛋白酵素電泳法 (gelatin zymography) 43
五、西方墨點法 (Western blot) 43
蛋白質萃取 (Protein extraction) 44
蛋白質定量 44
西方墨點法 (Western blot) 45
六、反轉錄酶-聚合酶連鎖反應 ( RT-PCR) 46
核糖核酸萃取 (RNA extraction) 46
反轉錄酶反應 ( RT ) 47
聚合酶連鎖反應 ( PCR ) 47
DNA 電泳 48
第五節 統計分析 49
第四章 結果 50
一、紫檀芪對A7r5細胞的細胞毒性結果 50
二、紫檀芪對A7r5細胞株分泌MMP-2之影響 50
三、紫檀芪對A7r5細胞株其MMP-2與內生性抑制劑TIMP-2之蛋白質表現的影響 51
四、紫檀芪對A7r5細胞株MMP-2之mRNA表現的影響 51
五、紫檀芪與MG132對A7r5細胞株之MMP-2蛋白質表現的影響 52
六、紫檀芪對A7r5細胞株其細胞爬行能力的影響 52
七、紫檀芪對A7r5細胞株其細胞遷移能力的影響 53
八、紫檀芪對A7r5細胞株其細胞侵入能力的影響 53
九、紫檀芪與氧化型低密度脂蛋白對A7r5細胞株其細胞遷移能力的影響 54
十、紫檀芪對A7r5細胞株其MAPK訊息傳遞路徑蛋白ERK1/2磷酸化表現的影響 55
十一、紫檀芪對A7r5細胞株其MAPK訊息傳遞路徑蛋白JNK1/2磷酸化表現的影響 55
十二、紫檀芪對A7r5細胞株其MAPK訊息傳遞路徑蛋白p38磷酸化表現的影響 56
十三、紫檀芪對A7r5細胞株其PI3K訊息傳遞路徑蛋白Akt磷酸化表現的影響 56
十四、紫檀芪與U0126 (MEK抑制劑) 對A7r5細胞株其MMP-2蛋白質表現的影響 57
十五、紫檀芪與U0126 (MEK抑制劑) 對A7r5細胞株其細胞遷移能力的影響 57
第五章 討論 59
第六章 結論 63
參考文獻 64

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