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研究生:林正浩
研究生(外文):Chang-Hau Lin
論文名稱:氯離子經由調控ERK1/2徑路的激酶活性以促進Thrombin引起血管平滑肌細胞COX-2的表現
論文名稱(外文):Cl--Dependent COX-2 Expression Induced by Thrombin in Vascular Smooth Muscle Cells : a Mechanism via Modulation of Kinase Activity in ERK1/2 Pathway
指導教授:馬蘊華
指導教授(外文):Yunn-Hwa Ma
學位類別:碩士
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:2007
畢業學年度:95
語文別:中文
論文頁數:61
中文關鍵詞:氯離子前列腺素血管平滑肌細胞
外文關鍵詞:ChlorideCOX-2ERK1/2ThrombinPGE2Vascular smooth muscle cells
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本實驗室過去曾發現,血管平滑肌細胞中ERK1/2的磷酸化具有對氯離子的依賴性。由於ERK1/2調控COX-2的表現,而COX-2可促進前列腺素的生成,並參與在發炎反應中,因此吾人測試以下假說:氯離子藉由促進ERK1/2徑路活性而促進由thrombin引發血管平滑肌細胞中COX-2的表現。將細胞處理高氯(120 meq/l)及低氯(20 meq/l)溶液,以thrombin刺激240分鐘後,高氯中COX-2的表現量為控制組的6.3 ± 0.9倍,而低氯中的反應為其44% (P<0.05)。而低氯中thrombin引發PGE2的產生為高氯中的74% (P<0.05)。此外,A23187引發的COX-2表現亦具有對氯離子的依賴性,低氯中COX-2的表現量為高氯中的58% (P<0.05)。PD98059能顯著的抑制thrombin及A23187引發的COX-2表現。更進一步的結果顯示,將細胞處理高氯及低氯溶液後,低氯中thrombin引發ERK1/2磷酸化的程度為高氯中的29% (P<0.05)。而sodium orthovanadate無法消弭高低氯之間ERK1/2磷酸化的差距,顯示氯離子並非藉由抑制tyrosine phosphatase而促進ERK1/2的磷酸化。而在試管中測試ERK1/2的激酶活性時發現,以NaHCO3及Na-gluconate取代NaCl會明顯的減少ERK1/2的激酶活性。因此,氯離子可能藉由增加血管平滑肌細胞中ERK1/2的激酶活性,而促進thrombin引發COX-2的表現增加及PGE2的製造。
We have demonstrated that Cl- enhances extracelluar signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in vascular smooth muscle cells (VSMC). ERK1/2 may regulate expression of a series of proteins, including cyclooxygenase-2 (COX-2) that produces prostaglandins and participates in inflammatory responses. We asked whether Cl- enhances thrombin-induced COX-2 expression via ERK1/2 pathway. In VSMC exposed to physiological salt solutions with 120 (high) vs. 20 (low) mEq/L of Cl-, treatment of thrombin (0.03 U/ml) for 4 hr induced 6.3 ± 0.9 vs. 2.8 ± 0.4 fold increase in COX-2 expression, respectively (n=4). In addition, A23187 (5 μM)-induced COX-2 expression were also Cl--dependent (n=4). Thrombin- or A23187-induced COX-2 expression were significantly inhibited by PD98059, a MEK1/2 inhibitor; further studies indicated that , thrombin induced 21.2 ± 4.3 vs. 6.2 ± 2.9 fold increase in ERK1/2 phosphorylation in 120 vs. 20 mEq/L of Cl-, respectively (n=3). Moreover, pretreatment of sodium orthovanadate, a tyrosine phosphatase inhibitor, did not affect Cl--dependent ERK1/2 phosphorylation induced by thrombin. Further studies indicated that Cl- replacement with bicarbonate or gluconate significantly attenuated kinase activity of phosphorylated ERK1/2 in vitro. Our results demonstrated that Cl- may exert an enhancing effect on the kinase activity in ERK1/2 pathway, resulting in an enhanced COX-2 expression in VSMC.
指導教授推薦書…………………………………………………………
口試委員會審定書………………………………………………………
授權書……………………………………………………………….i
誌謝…………………………………………………………………. ii
目錄…………………………………………………………………. iv
縮寫表………………………………………………………………….v
中文摘要…………………………………………………………….vii
英文摘要……………………………………………………………….viii
緒論…………………………………………………………………. 1
材料與方法…………………………………………………………. 13
結果…………………………………………………………………. 22
討論…………………………………………………………………. 33
圖表…………………………………………………………………. 43
參考文獻……………………………………………………….…… 54
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