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研究生:梁展榮
研究生(外文):Chan-Jung Liang
論文名稱:20-羥基二十烷四烯酸抑制血管平滑肌細胞增生及第二型環氧化酶表現之機制
論文名稱(外文):The Mechanisms of 20-HETE-Induced Inhibition of Cell Proliferation and Cyclooxygenase-2 Expression in Vascular Smooth Muscle Cells
指導教授:馬蘊華
指導教授(外文):Yunn-Hwa Ma
學位類別:博士
校院名稱:長庚大學
系所名稱:基礎醫學研究所
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:2008
畢業學年度:96
論文頁數:80
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20-羥基二十烷四烯酸 (20-hydroxyeicosatetraenoic acid; 20-HETE)是花生四烯酸 (arachidonic acid)經由細胞色素P450代謝後之長鏈不飽和脂肪酸,具有調控血管平滑肌功能的角色,本論文的主軸在於探討20-HETE對於抑制血管平滑肌細胞之增生及第二型環氧化酶 (cyclooxygenase-2; COX-2)表現之機制。 研究中利用胸腺嘧啶併入法及細胞計數來分析細胞生長速率,吾人發現20-HETE可抑制大鼠血管平滑肌細胞生長,並且有效的抑制血小板生長因子所誘發的細胞生長。 而此抑制細胞生長作用亦可見於人類血管平滑肌細胞。由於多種長鏈不飽和脂肪酸可促使細胞釋出轉化生長因子 (transforming growth factor-; TGF-),因此進一步探討TGF-於20-HETE作用的角色,發現對抗TGF-以及TGF- RII的抗體均可逆轉20-HETE所誘發之抑制細胞生長作用。經由酵素連結免疫吸附分析發現20-HETE可增加細胞培養液中所含的TGF-之濃度,而外加TGF-也會抑制血管平滑肌生長,然而同步定量聚合酶連鎖反應結果顯示20-HETE並不會增加細胞TGF-信使核糖核酸的表現量。 而血清及血小板生長因子所誘發的細胞週期素 D1表現量增加也可被20-HETE抑制,而此抑制作用亦可被TGF-的抗體所逆轉。 進一步在大鼠模式中測試P450代謝物的角色,發現P450的抑制劑1-aminobenzotriazole可以明顯促進氣球擴張術所引起的動脈內膜的增厚,此作用是否與抑制血管平滑肌增生的作用有關有待進一步研究。 除了抑制細胞增生以外,亦可抑制ATP誘發的COX-2蛋白質及信使核糖核酸表現量,而啟動子活性分析顯示20-HETE 可活化PPAR而促進含有PPRE的啟動子活性,由於PPAR-活化劑WY14643亦可抑制ATP誘發的COX-2表現量增加。 因此20-HETE抑制COX-2表現的作用極可能是透過活化PPAR而來。 進一步實驗發現20-HETE抑制ATP誘發的COX-2表現量增加的作用也可被PPAR-抑制劑MK-886所逆轉卻不受PPAR-的抑制劑(GW9662及BADGE)的影響。 而在轉染shRNA可有效的將血管平滑肌細胞的PPAR-表現抑制之後,20-HETE即喪失其對COX-2表現的抑制作用;而20-HETE仍能在轉染載體的對照組細胞抑制ATP誘發的COX-2表現。 由啟動子活性分析顯示,20-HETE抑制ATP誘發的COX-2啟動子活性增加可被PPAR-抑制劑MK-886所逆轉。 此外,在轉染PPAR-的shRNA之後,20-HETE即喪失其對COX-2啟動子活性的抑制作用;而20-HETE仍能在轉染載體的對照組細胞抑制ATP誘發的COX-2啟動子活性增加。 綜合以上研究,20-HETE具有抑制血管平滑肌增生及第二型環氧化酶表現的作用,20-HETE可能藉由影響血管平滑肌增生及發炎相關反應以調控血管疾病的產生。
20-hydroxyeicosatetraenoic acid (20-HETE), a P450 arachidonic acid metabolite, is an important regulator in vascular smooth muscle cells (VSMC). In present study, we aimed to determine the mechanisms of 20-HETE-induced inhibition of cell proliferation and cyclooxygenase-2 expression in VSMC. Incubation of R22D cells, a clonal VSMC, with 20-HETE for 24 hr attenuated [3H]-thymidine incorporation without causing release of lactate dehydrogenase. 20-HETE also inhibited platelet-derived growth factor (PDGF)-induced [3H]-thymidine incorporation in R22D cells and human VSMC. Since polyunsaturated may cause release of TGF-, we asked whether 20-HETE inhibited cell proliferation by releasing of TGF- Anti-TGF-β neutralizing antibody, but not nonspecific IgG, effectively reversed the attenuated [3H]-thymidine incorporation induced by 20-HETE. In addition, 20-HETE attenuated fetal bovine serum- and PDGF-induced expression of cyclin D1, a downstream effector of TGF-β1, which was reversed by anti-TGF-β antibody. Further studies demonstrated that 20-HETE may increase TGF-β release to a level enough to inhibit [3H]-thymidine incorporation without altering steady state mRNA level of TGF-β. The neointima formation induced by balloon-injured was enhanced by ABT, a P450 inhibitor which may inhibit 20-HETE production.
In addition to the effects on cell proliferation, pretreatment of 20-HETE (10 μM) significantly inhibited ATPγS-induced COX-2 mRNA and protein expression. Since 20-HETE may be a dual activator of PPAR, we asked whether 20-HETE induced inhibitory effect on COX-2 expression by activating PPAR. WY14643, a PPAR- ligand, mimicked the inhibitory effect of 20-HETE on COX-2 expression. Incubation with 20-HETE significantly increased the PPRE promoter activity suggesting that 20-HETE may be a PPAR activator. The inhibitory effect of 20-HETE on ATPγS-induced COX-2 expression was reversed by MK-886, a PPAR-α inhibitor, and by transfection of shPPAR-. In addition, ATPγS-induced COX-2 promoter activity, containing AP-1 site, was also inhibited by pretreatment of 20-HETE and was reversed by MK-886, a PPAR-α inhibitor, and by transfection of shPPAR-. Our results suggesting that 20-HETE may inhibit ATPγS-induced COX-2 expression via activation of PPAR-α. Taken together, 20-HETE may modulate the cell proliferation and inflammation of VSMC to regulate the development of cardiovascular diseases.
CONTENTS
指導教授推薦書
口試委員審定書
博士論文授權書 iii
CONTENTS iv
ACKNOWLEDGEMENTS v
ABBREVIATIONS vi
CHINESE ABSTRACT viii
ENGLISH ABSTRACT x
1. Introduction 1
2. Specific Aims 15
3. Materials and Methods 16
4. Results 23
5. Discussion 31
CONCLUSIONS 37
REFERENCES 38
FIGURES 52
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