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系統識別號 U0026-0812200914001684
論文名稱(中文) 細胞外基質合成酵素lysyl oxidase和prolyl 4-hydroxylase在人類腹主動脈瘤平滑肌細胞的表現
論文名稱(英文) The expression of extracellular matrix synthetic enzymes, lysyl oxidase and prolyl 4-hydroxylase, in human abdominal aortic aneurysm-derived vascular smooth muscle cells
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 95
學期 2
出版年 96
研究生(中文) 鄔孟陵
研究生(英文) Meng-Ling Wu
學號 t9694101
學位類別 碩士
語文別 英文
論文頁數 64頁
口試委員 口試委員-楊倍昌
口試委員-陳麗玉
指導教授-江美治
中文關鍵字 腹主動脈瘤  血管平滑肌  細胞外基質 
英文關鍵字 abdominal aortic aneurysms  smooth muscle cells  extracellular matrix  prolyl 4-hydroxylase  lysyl oxidase 
學科別分類
中文摘要 腹主動脈瘤在65歲以上人口的發生率為3-9%,一旦動脈瘤發生破裂時,其致死率高達50-70%。腹主動脈瘤主要的特徵包括,動脈管壁中層受到蛋白酵素的破壞,以及平滑肌細胞大量減少。截至目前對於腹主動脈瘤的研究大多在探討細胞外間質的破壞,而導致腹主動脈瘤的形成,但對於生成細胞外間質機制的變化,並不是很清楚。血管平滑肌細胞分泌細胞外間質,負責維持血管的結構。Lysyl oxidase (Lox)為一促進膠原蛋白與彈力蛋白的連結與堆積的酵素;Prolyl 4-hydroxylases (P4H)為膠原蛋白合成過程中的速率調控酵素,兩者都是調控細胞外間質合成與修補的關鍵酵素。現有的證據顯示活性氧分子(ROS)參與了腹主動脈瘤的形成,在本實驗室先前的研究發現,在Angiotensin II的刺激下由人類腹主動脈瘤檢體所培養出的血管平滑肌細胞,其超氧自由基(O2-)的生成與NADPH oxidase酵素活性皆有大量增加。因此我們假設在主動脈瘤培養出的血管平滑肌細胞中,超氧自由基的增加會對於Lox和P4H的表現或活性造成影響。本實驗利用由腹主動脈瘤檢體培養出的血管平滑肌細胞作為體外實驗的實驗組,並以冠狀動脈繞道手術時在升主動脈打洞所取得的檢體培養出的血管平滑肌細胞做為對照組。利用半定量RT-PCR來偵測三種P4H-α次單元體(α1、α2和α3)及P4H-β、Lox訊息核醣核酸的表現,除此之外也利用免疫轉漬法偵測P4H-β的表現。在腹主動脈瘤及冠狀動脈繞道手術所取得的檢體中,P4H-β次單元體蛋白的表現並無差異。在細胞培養的結果,實驗組及對照組細胞在P4H各次單元體及Lox 訊息核醣核酸的表現皆無顯著差異。而給予實驗組和對照組細胞Angiotensin II的刺激對P4H次單元體和Lox的訊息核醣核酸的表現則亦無影響。另外,以超氧自由基產生劑-LY83583刺激人類主動脈平滑肌細胞,會對P4H-α1次單元體訊息核醣核酸的表現產生抑制。由超氧自由基和一氧化氮的作用而產生的活性氧分子-過氧硝酸根(ONOO-)處理則顯著地抑制人類主動脈平滑肌中P4H-β次單元體蛋白的表現,而且抑制的效果隨著過氧硝酸根劑量的增加而增強,但另一種活性氧分子-過氧化氫對P4H-β次單元體蛋白的表現則沒有影響。由上面這些實驗結果顯示在血管平滑肌細胞中,P4H次單元體的表現會受到氧化壓力的影響而減少,但在目前的實驗條件下,Angiotensin II對於P4H次單元體的表現並無刺激作用,此外,對於Lox及P4H次單元體的表現在人類腹主動脈瘤的檢體中到底有沒有受到影響需要更進一步的確認。
英文摘要 Abdominal aortic aneurysm (AAA) occurs in 3~9% of the population over 65 years of age and exhibits a high mortality rate of 50% to 70% when rupture. Destruction of medial wall by proteinases and smooth muscle cell depletion are prominent characteristics of AAA. The mechanisms of extracellular matrix (ECM) degradation have been examined extensively, but much less are known about the regulatory mechanisms of ECM biosynthesis in AAA. Vascular smooth muscle cells (VSMCs) are responsible for synthesizing ECM proteins and maintaining structural integrity of the vascular wall. Lysyl oxidase (Lox), the enzyme initiating the covalent crosslinking of collagen and elastin in the extracellular space, and prolyl 4-hydroxylases (P4H), the rate-limiting enzyme for collagen biosynthesis, are key enzymes regulating ECM biosynthesis and repair. Reactive oxygen species (ROS) have been shown to be involved in the pathogenesis of AAA. Previous studies in our lab indicated that AAA-derived VSMCs exhibited greater capability of ROS production and higher NAD(P)H oxidase activity upon angiotensin II (Ang II) stimulation. Therefore, we hypothesize that increased ROS may modulate Lox and P4H expression in AAA-derived VSMCs. This study used cultured VSMCs derived from AAA specimens as an in vitro model with VSMC derived from the punctured ascending aortae at coronary artery bypass graft (CABG) surgery as control. The mRNA expression of three P4H-α subunits (α1, α2 and α3), P4H-β, and Lox was examined by semi-quantitative RT-PCR. In addition, P4H-β protein expression was examined by immunoblotting. At tissue level, no difference in P4H-β expression was detected between CABG and AAA specimens. In cultured cells, no significant differences in mRNA expression were detected between AAA- and CABG-derived VSMCs for all P4H subunits and Lox. Ang II treatment had no effects on P4H-α1, P4H-α2, P4H-α3, P4H-β or Lox mRNA expression in both AAA- and CABG-derived VSMCs. In human aortic VSMCs, LY83583, a superoxide anion-generating agent, decreased P4H-α1 mRNA expression. In addition, peroxynitrite, an ROS formed by the reaction between superoxide and nitric oxide, decreased P4H-β expression in a dose-dependent manner whereas H2O2 had no effect. These results suggest that oxidative stress may contribute to decreased P4H subunit expression in VSMCs but Ang II does not appear to be the stimulant under current experimental conditions. Further studies are needed to verify whether the expression of Lox and P4H subunits is affected in human AAA specimens.
論文目次 Chinese Abstract……………………………………………………Ⅱ
Abstract………………………………………………………………Ⅳ
Introduction……………………………………………………………1
Materials and Methods………………………………………………12
Results…………………………………………………………………31
Discussion ……………………………………………………………35
References ……………………………………………………………39
Figures…………………………………………………………………47
Tables …………………………………………………………………62
Appendix………………………………………………………………64
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