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系統識別號 U0026-0812200911493461
論文名稱(中文) 間質金屬蛋白酶在心血管疾病的角色探討
論文名稱(英文) Role of Matrix Metalloproteinases in Cardiovascular Disease
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 94
學期 1
出版年 95
研究生(中文) 劉秉彥
研究生(英文) Ping-Yen Liu
電子信箱 larry@mail.ncku.edu.tw
學號 s9890102
學位類別 博士
語文別 中文
論文頁數 117頁
口試委員 召集委員-林幸榮
口試委員-柯毓麟
口試委員-江福田
指導教授-陳志鴻
指導教授-吳華林
口試委員-廖朝崧
口試委員-葉宏ㄧ
中文關鍵字 間質金屬蛋白酶  多型性變異  抽菸  心肌梗塞  降血脂藥物  急性冠心症 
英文關鍵字 Matrix metalloproteinase  Polymorphism  Smoking  Acute coronary syndrome  Acute myocardial infarction  Statin 
學科別分類
中文摘要 在心肌梗塞形成的病理機轉中,血管斑塊的不穩定及破裂,血栓的急速形成,被公認是相當重要的因素。儘管血管斑塊破裂的真實機制尚未被完全了解,有一類重要的蛋白酶,間質金屬蛋白酶(matrix metalloproteinase, MMP),卻被認為是促成內皮細胞層上纖維帽不穩定與結構鬆散,導致血管斑塊裂縫形成,而產生心肌梗塞的重要因子。
事實上,在人類冠狀動脈的粥狀動脈硬化的血管斑塊上,間質金屬蛋白酶早已被廣泛的確認存在這些病理切片之中。其中的第三型間質金屬蛋白酶 (MMP3) 更是扮演重要的角色。多種刺激或改變會影響第三型間質金屬蛋白酶的活性。
本研究首先觀察急性心肌梗塞早期的第三型間質金屬蛋白酶與發炎指數的變化。我們發現在心肌梗塞初期24到48小時內,這些物質濃度有明顯升高之現象,這些升高程度和30天內死亡率有著正相關性。其次利用去氧核醣核酸序列分析儀來探索第三型間質金屬蛋白酶-1171 5A/6A基因變異,所影響的蛋白酶濃度和形成心肌梗塞 (年輕型<45歲) 發作的相關性。這一群台灣高危險病患的基因分析,具有相當的臨床價值及重要性,此基因變異在台灣年輕型心肌塞族群明顯地和抽煙有加成的危險性。而在平均約4年的追蹤期之間,我們記錄了這些年輕時罹患初次心肌梗塞的病患,再次發生冠狀動脈事件的機會。5A/6A基因變異病患有著最明顯的危險數值。同時,成功地戒煙可以大幅度減少帶有此因子變異病患的危險度。
更進一步,它和廣大的急性冠狀動脈症候群,這些病患血中濃度,冠狀動脈阻塞嚴重度也和基因背景有正相關。 這結果間接証實第三型間質金屬蛋白酶5A/6A基因變異是一個具有功能性的單核苷酸變異,會影響血管斑塊的穩定度而造成疾病。 在抽煙病患的血清給予離心後,與平滑肌細胞共同培養,在不同濃度的statin影響之下,平滑肌所分泌此第三型間質金屬蛋白酶隨著statin濃度增加而下降,暗示statin可以減少吸煙血清刺激平滑肌細胞產生第三型間質金屬蛋白酶的功能,藉此穩定受傷或不穩定的血管。
本論文的研究發現,間質金屬蛋白酶的活化,不僅是造成心肌梗塞的重要原因,同時也影響病患長期追蹤的預後。而第三型間質金屬蛋白酶-1171 5A/6A基因突變是台灣地區常見而重要的基因變異。而statin似乎可以減少第三型間質金屬蛋白酶的表現,具有血管保護效果。
英文摘要 Plaque rupture with thrombosis is well recognized as a critical factor in the pathogenesis of acute myocardial infarction (AMI). Although the mechanisms responsible for the plaque rupture are not clear, matrix metalloproteinase-3 (MMP3) may contribute to weakening of the cap and subsequent rupture. MMPs can degrade extracellular matrix and are identified extensively in human coronary atherosclerotic plaques. MMP3 can play a key role in rupture of atherosclerotic plaque, because it can cleave many of the extracellular matrix components as well as enhancing the activity of other MMPs.
Recently, a common polymorphism in the promoter region of the human MMP3 gene was described with 5 and 6 adenines (5A and 6A). The 5A/6A polymorphism in the promoter of the MMP3 gene had been documented as a novel pathogenetic risk factor for AMI in Japanese. In vitro assays of promoter activity revealed that the 5A allele had 2-fold higher promoter activity than the 6A allele.
In our studies, we found a very important variant at the promoter region of this MMP3 gene by PCR with direct DNA sequencing in normal healthy people and in patients with premature MI or acute coronary syndrome (ACS) in Taiwan. This variant also played as a genetic prognostic factor for the subsequent coronary events among these young MI patients. This genetic variant also interacted with smoking behavior for the onset and prognosis of ACS. By using an in vitro assay, we successfully demonstrated the ability on lowering MMP3 activity and other inflammatory markers of statins among smokers’ plasma samples.
In conclusion, we not only found an important genetic variant for the onset of MI in Taiwan; most importantly, but also a critical factor for the prognosis after the index MI. These results further support the important pathophysiologic roles of MMPs in the vascular remodeling and plaque stability.
論文目次 總目錄………………………………………………………………………………2
表與圖目錄…………………………………………………………………………4
本文常用縮寫及專有名詞對照表…………………………………………………8
中文摘要……………………………………………………………………………10
英文摘要……………………………………………………………………………12
第一章 緖論………………………………………………………………………13
1-1 急性心肌梗塞的病態生理學………………………………………………14
1-2 間質金屬蛋白酶在心血管系統的角色……………………………………16
1-3 第三型間質金屬蛋白酶的基因結構及突變和酵素活性的相關性………18
1-4 降血脂藥物血管保護效果與間質金屬蛋白酶的關係……………………20
1-5 本論文研究的特定目標……………………………………………………21
第二章 研究材料與方法………………………………………………………22
2-1 急性心肌梗塞病患組………………………………………………………23
2-2 早發性心肌梗塞病患組……………………………………………………23
2-3 正常對照組…………………………………………………………………24
2-4 心臟病危險因子的定義……………………………………………………24
2-5 急性冠狀動脈症候群病患組………………………………………………25
2-6 血中第三型間質金屬蛋白酶及發炎指數濃度之測定……………………26
2-7 第三型間質金屬蛋白酶-1171 5A/6A 基因突變之分析…………………27
2-8 降血脂藥物與平滑肌細胞培養……………………………………………29
2-9 統計方法……………………………………………………………………31
第三章 研究結果…………………………………………………………………33
3-1 急性心肌梗塞病患血中第三型間質金屬蛋白酶指數對病人預後的影響……………………………………………………………………………………34
3-2 第三型間質金屬蛋白酶-1171 5A/6A 基因變異與早發性心肌梗塞之間的關係…………………………………………………………………………………35
3-3 第三型間質金屬蛋白酶-1171 5A/6A 基因變異與心肌梗塞後再度急性化的關係………………………………………………………………………………37
3-4 第三型間質金屬蛋白酶-1171 5A/6A 基因變異與急性冠狀動脈症候群病患的關係……………………………………………………………………………39
3-5 降血脂藥物對抽煙患者血清內間質金屬蛋白酶活性及發炎指數的影響...43
第四章 討論………………………………………………………………………46
4-1 有關第三型間質金屬蛋白酶5A/6A 基因變異與心肌梗塞之間相關性的解
釋……………………………………………………………………………………47
4-2 第三型間質金屬蛋白酶5A/6A 基因變異與心肌梗塞在不同族群之間的差異性…………………………………………………………………………………48
4-3 過去第三型間質金屬蛋白酶基因變異與冠狀動脈狹窄的關係…………50
4-4 急性冠狀動脈症候群病患血中第三型間質金屬蛋白酶濃度與血管嚴重程度相關性研究………………………………………………………………………51
4-5 年輕型心肌梗塞長期追蹤, 與「抽煙習慣改變」對預後影響相關性研究..52
4-6 第三型間質金屬蛋白酶與Angiotensin-Ⅱ拮抗劑之間的關係……………54
第五章 結語………………………………………………………………………56
參考文獻……………………………………………………………………………59
發表著作……………………………………………………………………………74
榮譽與獎勵…………………………………………………………………………76
表與圖………………………………………………………………………………77
後記與感謝………………………………………………………………………116
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