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研究生:洪雅筠
研究生(外文):Ya-Yun Hung
論文名稱:探討轉殖SOD或catalase基因的人類主動脈內皮細胞對於腫瘤壞死因子刺激細胞表現黏附分子之機制
論文名稱(外文):The effects of overexpression of superoxide dismutase and catalase on the expression of adhesion molecules in TNFa-treated human aortic endothelial cells
指導教授:陳玉怜
指導教授(外文):Yuh-Lien Chen
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:解剖暨細胞生物學研究所
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:2003
畢業學年度:91
語文別:中文
論文頁數:123
中文關鍵詞:動脈硬化內皮細胞
外文關鍵詞:AtherosclerosisEndothelial Cells
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在動脈硬化的早期,可以發現白血球的黏附及移行到血管壁,並經由內皮細胞表現細胞表面黏附分子,而上述這些過程不但在動脈硬化的病理過程中扮演一個重要角色,也跟內皮細胞(Endothelial Cell)的發炎(Inflammatory)反應息息相關。透過已知的證據顯示,發炎反應可經由細胞內的氧化壓力所觸發,而前發炎細胞素-腫瘤壞死因子(Tumor Necrosis Factor-alpha; TNF-a)則可以經由產生活性氧族群(ROS; Reactive Oxygen Species)來引起動脈硬化中細胞黏附分子的產生。所以我們這次的研究中,是利用腺病毒(Adenovirous; Ad)轉殖人類銅/鋅型超氧物歧化酶(Cu/ZnSOD)及過氧化氫酶(Catalase)的基因至人類主動脈內皮細胞(Human Aortic Endothelial; Cell HAEC),來觀察這二種抗氧化酵素對於TNF-a刺激人類主動脈內皮細胞,導致ROS的產生及細胞黏附分子表現的機制。在實驗結果中,(1)利用腺病毒轉殖Cu/ZnSOD及Catalase 基因至人類主動脈內皮細胞,Cu/ZnSOD及Catalase可在內皮細胞大量的表現並且皆位於細胞質內。(2)以TNF-a 刺激內皮細胞,會促進細胞表現大量的Superoxide Anion (O2.-)及H2O2 (Hydrogen Peroxide)。轉殖Cu/ZnSOD可以減少O2.-的產生,轉殖Catalase可以減少H2O2的產生,而共同轉殖Cu/ZnSOD及Catalase可以減少H2O2的產生。(3)利用TNF-a 刺激內皮細胞,會大量的表現ICAM-1 (Intercellular Adhesion Molecules-1)和VCAM-1 (Vascular Cell Adhesion Molecule-1),並可經由轉殖AdSOD (Adenovirus Cu/ZnSOD)及AdCO (Adenovirus Co-transfection)顯著抑制。(4)以TNF-a刺激內皮細胞,可以誘導JNK1/2 (c-Jun NH2-terminal Kinase 1/2)、ERK1/2 (Extraceullar Signal-Regulated Kinase 1/2)、p38MAPK (p38 Mitogen Activated Protein Kinase)、AP-1 (Activator Protein-1)及NF-kB(Nuclear Factor-kappa B)的表現;在ERK1/2部分,轉殖腺病毒並不能抑制其表現量;而轉殖AdSOD則能明顯的抑制JNK1/2、p38MAPK、AP-1及NF-kB的活化,但轉殖AdCAT僅能抑制p38MAPK,在轉殖AdCO (Adenovirus Co-transfection)部分則能抑制p38MAPK、JNK1/2、AP-1及NF-kB。而單獨加入p38MAPK及JNK1/2的抑制劑即能抑制ICAM-1與VCAM-1的表現,而加入TNF-a刺激後,在VCAM-1方面,主要被p38MAPK及JNK1/2的抑制劑所抑制,而ERK1/2的抑制劑為部分的影響,但在ICAM-1方面僅被p38MAPK及JNK1/2的抑制劑所抑制。因此我們可以推論,以TNF-a刺激內皮細胞可以產生大量的ROS,並透過JNK1/2、p38MAPK這二個訊息傳遞路徑去活化AP-1及NF-kB等轉錄因子,使ICAM-1、VCAM-1表現增加。綜合上述,經由轉殖不同抗氧化酵素的腺病毒,可以透過不同機制的影響來達到保護細胞的效果。
Attachment and migration of leukocytes into the vessel wall are early events in atherogenesis. Expression of cell adhesion molecules by the arterial endothelium plays a major role in atherosclerosis. Several studies also indicated that local inflammation mediated by intracellular oxidative stress may trigger atherosclerosis. The pro-inflammatory cytokine TNF-a (Tumor Necrosis Factor-alpha) could induce ICAM-1 (Intercellular Adhesion Molecule-1) and VCAM-1 (Vascular Cell Adhesion Molecule-1) in atherosclerotic lesions. In the present study, adenovirus-mediated gene transfer of Catalase or Cu/ZnSOD in HAECs (Human Aortic Endothelial Cells) , was used to examine the production of ROS (Reactive Oxygen Species) and the expression of endothelium—leukocyte adhesion molecules by TNF-a-treated HAECs. The following results were obtained in this study: (1) Transfection AdCu/ZnSOD (Adenovirus Cu/ZnSOD) and AdCAT (Adenovirus Catalase) into endothelial cell increased the expression of Cu/ZnSOD and Catalase in endothelial cytosol. (2) The increased expression of O2.- (Superoxide Anion) and H2O2 (Hydrogen Peroxide) were also detected in the endothelial cell with the stimulation of endothelial cell by using TNF-a stimulation. Transfection of AdCu/ZnSOD decreased the production of O2.-, while the transfection of AdCAT decreased that of H2O2. (3) With the stimulation of endothelial cell using TNF-a, the increased expression of ICAM-1 and VCAM-1 were also detected. It is also decreased the expression of adhesion molecules with the transfection of AdSOD and AdCO (Adenovirus Co-transfection). The transfection of AdCAT decreased the expression of adhesion molecules. (4)The inducing of JNK1/2 (c-Jun N-terminal Kinase 1/2)、ERK1/2 (Extraceullar Signal Regulated Kinase 1/2)、p38MAPK (p38 Mitogen Activated Protein Kinase)、AP-1 (Activator Protein-1) and NF-kB (Nuclear Factor-kappa B)were investigated in this study with the stimulation of endothelial cell using TNF-a. The transfection AdSOD has an effect on decreasing the activation of JNK1/2、 p38MAPK、AP-1 and NF-kB. The expression of VCAM-1 decreased with the inhibitors of p38MAPK and JNK1/2. Only the inhibitors of p38MAPK and JNK1/2 have the effect on decreasing the expression of ICAM-1. According to this study, the production of ROS will be increased with the stimulation of endothelial cell using TNF-a. When JNK1/2 and p38MAPK were activated, the expression of ICAM-1、VCAM-1 increased. Our results suggested that transfection adenovirus with different antioxidative enzymes could exert cytoprotective effects by means of different mechanisms.
縮寫表
中文摘要………………………………………………………………... 1
英文摘要………………………………………………………………... 3
壹、緒論
一、動脈硬化的成因………………………………………………... 6
二、動脈硬化與腫瘤壞死因子的相關性…………………………... 8
三、動脈硬化與活性氧族群(Reactive Oxygen Species)的相關性….9
四、動脈硬化與氧化壓力的相關性
(一)超氧歧化酶 (Superoxide Dismutase; SOD)………………...11
(二)過氧化氫酶 (Catalase)……………………………………...13
五、動脈硬化與細胞黏附分子的相關性…………………………….13
六、動脈硬化與Mitogen Activated Protein Kinase(MAPK)的相關
性....................................................................................................16
七、動脈硬化與轉錄因子(Transcription Factor) 的相關性
(一)NF-kB(Nuclear Factor-kappa B)…………………………18
(二)AP-1 (Activator Protein-1)…………………………………..19
八、腺病毒載體(Adenovirus Vector)………………………………20
九、研究動機………………………………………………………….22
貳、材料與方法
一、儀器設備………………………………………………………….24
二、實驗材料與試劑………………………………………………….25
三、實驗用溶液配方………………………………………………….28
四、實驗方法………………………………………………………….31
(一)共軛焦顯微鏡術(Confocal Microscopy)
(二)腺病毒載體製備(Adenoviral Construction)
(三)腺病毒轉殖基因至人類主動脈內皮細胞
(四)西方墨漬法(Western Blot)
(五)Catalase活性測定(Catalase Assay)
(六)Superoxide dismutase(SOD)活性測定(SOD Assay)
(七)細胞存活率 (MTT Assay)
(八)細胞內superoxide產量的測定(Determination of Intracellular
Superoxide Anion)
(九)細胞內H2O2產量的測定(Determination of Intracellular
H2O2)
(十)細胞酵素連結免疫吸附分析法(Cell ELISA)
(十一)內皮細胞/單核球細胞粘附試驗(Endothelial Cells/Monocyte Adhesion Assay)
叁、實驗結果……………………………………………………………47
肆、討論與結論…………………………………………………………65
附圖………………………………………………………………..74
參考文獻…………………………………………………………100
附件………………………………………………………………114
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