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研究生:吳俊威
研究生(外文):Chun-Wei Wu
論文名稱:白藜蘆醇影響人類臍靜脈內皮細胞與小鼠胸主動脈中表現黏附因子的效果與分子機轉
論文名稱(外文):The Effect of resveratrol on the ICAM-1 expression of TNF-α-treated Endothelial Cells and Aortas and its related Mechanisms
指導教授:陳玉怜
口試委員:江美治王懷詩李繼源吳建春
口試日期:2014-07-14
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:解剖學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:2014
畢業學年度:102
語文別:中文
論文頁數:89
中文關鍵詞:白藜蘆醇動脈硬化抗發炎黏附因子MAPKsNF-kBAMPK
外文關鍵詞:ResveratrolatherosclerosisinflammationAdhesion moleculeMAPKsNF-kBAMPK
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心血管疾病已經成為全球最主要的健康問題之一,而且已連續三年成為台灣十大死因前三名,不僅如此,根據世界衛生組織統計,全球每年約有1650萬人死於心血管疾病。心血管疾病已被證實屬於一種慢性的發炎反應,當血管受到刺激時,會促使內皮細胞釋放細胞激素與表現ICAM-1等黏附因子。Resveratrol是可以經由葡萄、紅酒與許多植物中萃取出的天然物質,它是一種非黃酮的多酚類化合物(natural nonflavonoid polyphenolic compound)。近年來許多研究指出resveratrol有抗氧化及抗發炎的功能,進而防止心血管疾病的發生,但其中的機制仍尚未明瞭,因此我們的研究主軸是探討resveratrol對血管內皮細胞抗發炎的效果與機制。我們使用人類臍靜脈內皮細胞作為in vitro的實驗材料,實驗證明,在人類臍靜脈內皮細胞中TNF-α會顯著誘發ICAM-1表現,而先給予resveratrol處理再投予TNF-α則可以有效抑制由TNF-α誘發的ICAM-1表現。在探討機制的研究中發現,TNF-α會促使p-ERK、p-JNK、p-p38、p-IκB、p-p65及Ac-p65的表現量上升,而預先以resveratrol處理的細胞會抑制p-ERK、p-p38、p-IκB、p-p65及Ac-p65的表現。實驗進一步發現加入JNK、p-38與p-65的抑制劑,再加入TNF-α刺激會降低ICAM-1的表現,換句話說,在人類臍靜脈內皮細胞中,TNF-α是經由JNK、p38與NF-κB這三個路徑去誘發ICAM-1的表現,由此推論resveratrol可以藉由影響p38與NF-κB進而抑制TNF-α所誘發的ICAM-1表現。不僅如此,我們也發現resveratrol可以有效降低單核球與內皮細胞黏附的情形。在轉錄因子部分,resveratrol可以顯著抑制NF-κB p65在細胞核的表現及其與ICAM-1基因的結合活性(binding activity)。我們的實驗也發現,resveratrol可以活化AMPK,並且再加入AMPK活化劑後,可以有效降低TNF-α所誘發的ICAM-1的表現,顯示,resveratrol也可以藉由活化AMPK而抑制ICAM-1的表現。除此之外我們也發現當AMPK被活化時會誘發p-p38表現,而p-p38會誘發p-IκB的表現,綜合以上結論,說明resveratrol對於p38、AMPK與IκB可以藉由直接或間接的方式進行調控並影響ICAM-1的表現。在動物實驗方面,我們使用8週的成年雄性C57BL/6J小鼠,將其分為四組:DMSO控制組、TNF-α刺激組、resveratrol治療組與resveratrol組。給予resveratrol、TNF-α與DMSO後,取其胸主動脈進行實驗,結果顯示,在小鼠的胸主動脈中,resveratrol也可以抑制ICAM-1的表現。我們也使用Apo-E缺陷小鼠進行實驗,實驗發現有給予resveratrol組的血液中sICAM-1、三酸甘油脂與總膽固醇的表現皆比未給予resveratrol組低,並且在動脈硬化病灶處ICAM-1與TNF-α的表現也較低。綜合以上實驗結果,我們認為resveratrol對TNF-α誘發的ICAM-1有良好的抑制效果,顯示也許resveratrol可以藉由抗發炎進而達到預防心血管疾病的發生。

Resveratrol, a natural polyphenolic compound, is isolated from grapes, peanuts and other plants. Accumulating evidence indicates that resveratrol exerts its beneficial effects on cardiovascular system by its antioxidative and anti-inflammatory properties. However, the detailed mechanisms of its effects need to be investigated. Therefore, we focused on its effects on the expression of intercellular adhesion molecule-1 (ICAM-1) in tumor necrosis factor-α (TNF-α)-treated human umbilical vein endothelial cells (HUVECs) and its related mechanisms. TNF-α significantly induced ICAM-1 mRNA and protein expression in HUVECs and the effect was inhibited by pretreatment with resveratrol. TNF-α rapidly induced the phosphorylation of extracellular-regulated kinase (ERK), p38 MAPK, c-Jun N-terminal kinase (JNK) , inhibitory protein kappa B (IκB), nuclear factor kappa B (NF-κB) and NF-κB acetylation in HUVECs. Pretreatment with SP600125 (a JNK inhibitor), SB203580 (a p38 inhibitor) and Bay-117082 (a NF-κB inhibitor) significantly reduced TNF-α-induced ICAM-1 expression, whereas PD98059 (an ERK1/2 inhibitor) has no effect. Furthermore, pretreatment with resveratrol effectively reduced the phosphorylation of ERK, p38 MAPK, NF-κB and NF-κB acetylation, but not JNK phosphorylation in TNF-α-treated HUVECs. In addition, the nuclear translocation and DNA binding activity of NF-κB was also induced by TNF-α and the effects were inhibited with resveratrol pretreatment as demonstrated by immunostaining and EMSA. Moreover, resveratrol can also reduce monocyte adhesion to TNF-α-treated HUVECs. AMP-activated protein kinase (AMPK) can suppress inflammation. We also found that resveratrol can induce phosphorylation of AMPK in HUVECs. Moreover pretreatment with AICAR (an AMPK activator) significantly reduced TNF-α-induced ICAM-1 expression. In animal study, the mice were randomly divided into four groups: (1) the DMSO group, (2) the TNF-α group, (3) the TNF-α plus resveratrol group, and (4) the resveratrol group. DMSO and resveratrol (10 mg/kg) were given by intraperitoneal injection for five days and then mice were challenged with TNF-α (10 μg/kg) for the next three days. The thoracic aortas were isolated for paraffin section and the expression of ICAM-1 and CD31 was detected on serial sections by immunohistochemistry. We observed that administration of resveratrol effectively attenuated ICAM-1 expression in ECs in thoracic aortas of TNF-κ-treated mice. Our data showed that resveratrol inhibits TNF-κ-induced activation of NF-κB and p38MAPK, thereby suppresses ICAM-1 expression. Taken together, these results suggest that resveratrol may prevent the development of atherosclerosis and inflammation.

中文摘要 I
英文摘要 III
壹、緒論
一、前言 1
二、動脈硬化的成因與病理機轉 1
三、動脈硬化與內皮細胞的關係 2
四、動脈硬化與腫瘤壞死因子的關係 3
五、動脈硬化與細胞黏附因子的關係 4
六、動脈硬化與MAPKs的關係 5
七、動脈硬化與轉錄因子NF-κB的關係 6
八、動脈硬化與AMPK的關係 7
九、動脈硬化與氧化壓力的關係 8
十、代表動脈硬化或發炎反應所採用動物模式 9
十一、白藜蘆醇 (Resveratrol) 10
十二、研究動機 12
貳、實驗材料
一、儀器設備 14
二、實驗材料與試劑 14
三、實驗用溶液配方 19
參、實驗方法
一、人類臍靜脈內皮細胞培養 22
二、細胞活性分析法 22
三、西方點墨法 23
四、免疫細胞化學染色法 26
五、細胞核與細胞質蛋白萃取 26
六、測定mRNA表現 27
七、凝膠遷移 29
八、ROS測定 30
九、內皮細胞/單核球細胞黏附試驗 30
十、動物實驗 31
十一、組織石蠟包埋 31
十二、免疫組織化學染色 32
十三、數據統計分析 33
肆、實驗結果
一、以50μM的resveratrol處理對人類臍靜脈內皮細胞不具毒害性 34
二、Resveratrol減少TNF-α誘發人類臍靜脈內皮細胞ICAM-1的產生 34
三、Resveratrol減少TNF-α誘發人類臍靜脈內皮細胞ICAM-1 mRNA的表現 35
四、Resveratrol抑制TNF-α刺激人類臍靜脈內皮細胞中p38 MAPK的磷酸化 35
五、TNF-α刺激人類臍靜脈內皮細胞ICAM-1是透過MAPKs訊息傳遞 36
六、Resveratrol會抑制TNF-α刺激人類臍靜脈內皮細胞中p-IκB的表現 36
七、Resveratrol抑制TNF-α刺激人類臍靜脈內皮細胞中NF-κB的磷酸化情形 36
八、TNF-α刺激人類臍靜脈內皮細胞ICAM-1是透過NF-κB傳遞 37
九、Resveratrol抑制NF-κB p-65在細胞核中的表現 37
十、Resveratrol抑制轉錄因子NF-κB的活性 38
十一、Resveratrol抑制TNF-α刺激人類臍靜脈內皮細胞中p65乙醯化情形 39
十二、MAPKs在TNF-α處理人類臍靜脈內皮細胞會誘發p-IκB的表現 39
十三、Resveratrol抑制monocyte黏附至TNF-α處理的人類臍靜脈內皮細胞 39
十四、Resveratrol在人類臍靜脈內皮細胞中會活化AMPK 40
十五、Resveratrol促進TNF-α抑制人類臍靜脈內皮細胞中p-AMPK與SIRT-1的表現 40
十六、在人類臍靜脈內皮細胞中AMPK的活化會抑制TNF-α誘發ICAM-1表現 41
十七、在人類臍靜脈內皮細胞中SIRT-1的活化不會抑制TNF-α誘發ICAM-1表現 41
十八、AMPK在TNF-α處理人類臍靜脈內皮細胞中會抑制p-p38與p-IκB的表現 41
十九、Resveratrol抑制TNF-α誘發人類臍靜脈內皮細胞中ROS的表現 42
二十、Resveratrol 減少TNF-α刺激C57BL/6小鼠體內ICAM-1的影響 42
二十一、Resveratrol 減少Apo-E缺陷小鼠血液中sICAM-1、三酸甘油脂與總膽固醇的表現 43
二十二、Resveratrol 減少Apo-E缺陷小鼠中主動脈弓病灶處ICAM-1與TNF-α的表現 43
伍、討論與結論 44
陸、參考文獻 50
柒、附圖
圖一、以細胞活性分析法觀察resveratrol對人類臍靜脈內皮細胞存活率的影響 65
圖二、以西方點墨法觀察resveratrol對人類臍靜脈內皮細胞產生ICAM-1的影響 66
圖三、以免疫細胞螢光染色法觀察resveratrol對人類臍靜脈內皮細胞產生ICAM-1的影響 67
圖四、Resveratrol對人類臍靜脈內皮細胞ICAM-1 mRNA表現情形的影響 68
圖五、Resveratrol對人類臍靜脈內皮細胞中由TNF-α 誘發之MAPKs訊息傳遞的影響 69
圖六、TNF-α刺激人類臍靜脈內皮細胞表現ICAM-1是透過JNK及P38訊息傳遞 70
圖七、Resveratrol對人類臍靜脈內皮細胞中由TNF-α 誘發之p-IκB表現的影響 71
圖八、Resveratrol對人類臍靜脈內皮細胞中由TNF-α 誘發之NF-κB p65訊息傳遞的影響 72
圖九、TNF-α刺激人類臍靜脈內皮細胞ICAM-1是透過NF-κB訊息傳遞 73
圖十、以西方點墨法觀察細胞核內NF-κB p65的表現情形 74
圖十一、以免疫細胞螢光染色法觀察resveratrol抑制NF-κB p65在細胞核的表現情形 75
圖十二、以EMSA檢測resveratrol抑制轉錄因子NF-κB的活性 76
圖十三、Resveratrol對人類臍靜脈內皮細胞中由TNF-α 誘發之Ac-p65表現的影響 77
圖十四、以西方點墨法觀察在人類臍靜脈內皮細胞中MAPKs與NF-κB之間的交互關係 78
圖十五、利用adhesion assay觀察單核球與人類臍靜脈內皮細胞間的黏附情形 79
圖十六、Resveratrol對人類臍靜脈內皮細胞中AMPK磷酸化表現的影響 80
圖十七、Resveratrol對人類臍靜脈內皮細胞中由TNF-α 抑制之p-AMPK與SIRT-1表現的影響 81
圖十八、AMPK的活化對對人類臍靜脈內皮細胞中由TNF-α 誘發ICAM-1表現的影響 82
圖十九、SIRT-1的活化對對人類臍靜脈內皮細胞中由TNF-α 誘發ICAM-1表現的影響 83
圖二十、活化AMPK對人類臍靜脈內皮細胞中由TNF-α誘發之MAPKs與NF-κB訊息傳遞的影響 84
圖二十一、Resveratrol對人類臍靜脈內皮細胞中ROS表現的影響 85
圖二十二、以免疫組織化學染色法觀察resveratrol 對TNF-α刺激C57BL/6小鼠主動脈表現ICAM-1的影響 86
圖二十三、以酵素連結免疫吸附分析法及比色法觀察resveratrol對於Apo-E缺陷小鼠體內sICAM-1、三酸甘油脂與總膽固醇表現的影響 87
圖二十四、以免疫組織化學染色法觀察resveratrol 對Apo-E缺陷小鼠主動脈弓動脈硬化處表現ICAM-1及TNF-α的影響 88
圖二十五、以簡圖表示resveratrol與各路徑間的關係 89

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