臺灣博碩士論文加值系統

血管平滑肌細胞的移行 (migration)、增生 (proliferation) 及細胞外基質蛋白 (extracellular matrix) 之合成等活化作用在粥狀動脈硬化 (atherosclerosis) 及許多心血管疾病的病理過程中，扮演著重要的角色。在這些疾病的進展中，受損的血管會釋出具有促進血管平滑肌細胞生長及趨化性 (chemotactic) 的血小板衍生生長因子 (PDGF-BB)，並藉由活化其細胞膜上的酪氨酸激酶受體 (tyrosine kinase receptor)-PDGF受體- (PDGFR-)，而引起血管平滑肌細胞的移行及增生作用。白楊素 (chrysin) 是一種類黃酮的成份，可以由許多種的植物、蜂蜜及蜂膠中萃取獲得，已有許多的研究顯示白楊素具有抗發炎、抗腫瘤及抗氧化的作用，然而有關於白楊素對於血管平滑肌細胞功能的影響則少有研究探討。因此，我們在此研究中探討白楊素對於血管平滑肌細胞功能的影響，包括血管平滑肌細胞與細胞外基質蛋白的交互作用、血管平滑肌細胞的增生及移行作用。實驗的結果顯示，白楊素具有濃度相關性的抑制 PDGF-BB 引發血管平滑肌細胞移行及增生的作用，且當白楊素的濃度在 20 M 時具有顯著抑制細胞移行及增生的效果。進一步探討的結果顯示，白楊素藉由抑制 PDGF受體-及其下游細胞內訊息傳遞蛋白的磷酸化，而具有抑制血管平滑肌細胞移行及增生的作用。白楊素具有時間相關性及濃度相關性的抑制 PDGF-BB 引發 PDGF受體-β、PLC、PI3K、Akt、p38 及 JNK 磷酸化的作用，但是對於 ERK1/2 的磷酸化則無抑制作用。白楊素也會減少經由 H2O2引發之 PDGF 受體-的活化及細胞內氧自由基的含量。而另一方面，在 20 M 的高濃度下，白楊素並不影響血管平滑肌細胞與細胞外基質蛋白的貼附作用，以及 PDGF-BB 引發血管平滑肌細胞釋出基質金屬蛋白酶 (matrix metalloproteinases, MMPs) 的活性。除此之外，白楊素對於凝血酶 (thrombin) 引發PLC、PI3K、Akt 等細胞內訊息傳遞的活化並無抑制的作用，顯示白楊素對於 PDGF 的作用具有相當的專一性。由於血管平滑肌細胞的增生及移行作用，在粥狀動脈硬化及心血管疾病的致病機轉中扮演著關鍵性的角色，因此我們推測白楊素在心血管疾病的預防上，或許有其助益。

Vascular smooth muscle cell (SMC) migration, proliferation and extracellular matrix (ECM) synthesis play important roles in the development and progression of atherosclerosis and various vascular diseases. During the processes, an important growth factor produced in the injured vascular wall, namely platelet-derived growth factor-BB (PDGF-BB), is a potent mitogen and chemotactic factor for SMCs. It can initiate a multitude of biological effects through the activation of transmembrane protein tyrosine kinase receptor-PDGF receptor- (PDGFR-) contributing to SMC migration and proliferation. Chrysin, a flavonoid extracted from plants, honey and propolis, has been demonstrated to have anti-inflammatory, anti-cancerous and anti-oxidative effects. However, the effect of chrysin on functions of SMCs remains largely unknown. In the present study, the effects of chrysin on SMC-ECM interaction, SMCs proliferation and migration were investigated. Our results indicated that chrysin inhibited PDGF-BB-induced migration and proliferation in vascular SMCs in a concentration-dependent manner. 20 M of chrysin is sufficient to elicit its inhibitory effect. A further analysis revealed that chrysin is acting through inhibition of phosphorylation of PDGFR- and its downstream intracellular signaling kinases. Chrysin time- and concentration-dependently inhibited PDGF-BB-induced phosphorylation of PDGFR-β, PLC, PI3K, Akt, p38 and JNK, but scarcely inhibited ERK1/2 phosphorylation. Moreover, chrysin attenuated H2O2-induced PDGFR-activation and intracellular reactive oxygen species level. However, chrysin did not inhibit SMC adhesion to ECM proteins and PDGF-BB-induced SMC matrix metalloproteinase (MMPs) activity even at a higher concentration (20 M). In a paralleled experiment, chrysin did not affect thrombin-induced signaling, including PLC PI3K and Akt activation, suggesting its relative specificity for PDGF. As SMCs migration and proliferation are critical events during atherogenesis, our findings suggest that chrysin might have beneficial effects in preventing cardiovascular diseases.

中文摘要 i
英文摘要 iii
縮 寫 對 照 表 v
誌 謝 vii
第一章 緒 言 1
第二章 文獻回顧 3
一. 粥狀動脈硬化的病理機轉 3
二. 血管平滑肌細胞的活化與心血管疾病之關聯 5
三. 血小板衍生生長因子 (Platelet-derived growth factor, PDGF) 與血管平滑肌細胞活化之病理關聯 7
四. H2O2與血管平滑肌細胞活化之病理關聯 9
五. 類黃酮 (flavonoids) 之心血管保護作用 11
六. 白楊素 (chrysin) 13
第三章 材料與方法 18
一. 實驗設計 18
二. 材料與試劑 18
三. 實驗方法 19
(一) 大鼠動脈血管平滑肌之製備與培養 19
(二) 細胞貼附之檢測 (Cell adhesion assay) 20
(三) 細胞增生之檢測 (Proliferation assay) 21
(四) 細胞移行之檢測 (Migration assay) 22
(五) 細胞抽取物的製備及西方墨點轉漬法 (Cell lysate preparation and Western immunoblot analysis) 23
(六) 以流式細胞儀偵測細胞內自由基之平均螢光強度 25
(七) Gelatin zymography 26
(八) 統計分析方法 27
第四章 結果 28
第五章 討論 39
第六章 結論 46
第七章 參考文獻 69

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