負電性低密度脂蛋白L5和急性冠心症候群之冠狀動脈斑塊演變的關聯性

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題名:	負電性低密度脂蛋白L5和急性冠心症候群之冠狀動脈斑塊演變的關聯性 Potential Link of L5 to Coronary Plaques in Acute Coronary Syndrome
作者:	陳珠璜(Chu-Huang Chen)
貢獻者:	醫學院臨床醫學研究所;中國附醫L5研究中心
關鍵詞:	負電性低密?脂蛋白;心肌細胞;內皮細胞;趨化因子;electronegative low-density lipoprotein;cardiomyocytes;endothelial cells;chemokines
日期:	2012-07-31
上傳時間:	2013-01-25 15:30:45 (UTC+8)
摘要:	近??，動脈硬化疾病被視為是一種慢性發炎疾病，而其中低密?膽固醇(LDL)之代謝?常，被認為是致病的一個顯著危險因子。然而，由於血漿中之低密?膽固醇絕對值的高低，無法真正用?衡?冠?動脈疾病(CAD)形成之風險，目前學界依舊致?於尋找真正造成動脈硬化的特定低密?膽固醇。過去許多研究顯示，氧化低密?膽固醇 (Oxidized LDL)與小而密低密?膽固醇 (small dense LDL)和冠?動脈疾病之形成相關。但這?者至今仍未直接從人?血漿分?出?，並由此?檢視其致病機轉。相反地，陰電性低密?膽固醇 (electronegative LDL)，分佈於人?血漿中低密?膽固醇，對體外培養之血管細胞，有促進動脈硬化之獨特性質。我們研究團隊?用陰?子交換色譜法 (anion-exchange chromatograpgy)，從心血管疾病高風險族群的病患血漿中，分?出一種陰電性最強的極端型態陰電性低密?膽固醇，並將之名為L5。L5 ?但在健康人體內非常稀少，並且和人工製造之氧化低密?膽固醇同樣地，能促使血管細胞產生動脈硬化之變化。其中最重要的是，最近我們從台中中國醫藥大學附設醫院住院之心血管疾病患者，發現其血漿中L5 之濃?顯著升高，且經由冠?動脈介入治?或藥物治?後，其濃 ??逐漸下?。此外，在急性心肌梗?患者，我們經由血栓抽吸得到許多冠?動脈組織內容物，分析後也顯示L5 在冠?動脈急性血栓的形成上，扮演相當重要的角色。根據上述突破性的發現，我們提出本全方位的研究計畫，擬證實在急性冠心症候群(Acute coronary syndrome)，尤其是ST 段上升急性心肌梗?(ST elevation myocardial infarction) 患者，觀察L5 在冠?動脈斑塊形成與斑塊?穩定方面所扮演的角色。這個研究計畫包含四個主要目標，分別由?床、化學、細胞分子、與組織學各角?，探討這個在醫學上非常重要的議題。在目標一當中，我們將探討L5 濃?在急性心肌梗?的病程中，是否真的會顯著升高。此外，在這樣的病患族群，我們也將探討介入治?前後L5 濃?的變化，能否當作L5 存在斑塊中的證據。目標二與目標三，則被設計?檢驗L5 在斑塊形成的特定病?機轉上，所扮演的角色。其中，我們特別要研究L5 在低密?膽固醇之聚集、單核細胞（monocyte）清道夫受體(scavenger receptor)之誘發、明膠酵素（gelatinase）之過?活性、與血小板之活化或聚集等機轉上所產生的作用。目標四則是設計用?廣泛地檢驗冠?動脈內的組織，確認L5 在急性冠心症?床病?方面所扮演的角色。這個研究計畫將全部在台灣中國醫藥大學附設醫院執?，此研究成果，將有助於解決這個長久以 ?，在公衛上受到高?關注卻未解決的問題。而此研究之結?，也將對未?有關心血管疾病診斷與治?的研究，提供?空前準確的嶄新線?與方向。由於這個議題具有無庸置疑的重要性，因此這個研究計畫的進?，也將具有真正的迫?性。我們的目標，是成為全世界第一個團隊，?僅確認真正造成急性冠心症的低密?膽固醇本質，也希望基於上述基礎，能針對這個??在台灣或全世界?受到普遍關注的公衛議題，繼續?導相關? 域的研究。 Deranged metabolism of low-density lipoprotein (LDL) is considered the preeminent modifiable risk factor for atherosclerotic disease, widely viewed to be a chronic inflammatory disorder. However, the search for a circulating atherogenic LDL species continues, as the risk for developing coronary artery disease (CAD) cannot be measured by the absolute LDL cholesterol concentrations in the plasma. Oxidized LDL and small, dense LDL are associated with CAD, but neither has been retrieved from human plasma to undergo mechanistic scrutiny. Electronegative LDL is a subclass of human plasma LDL that has been found to exhibit atherogenic properties in cultured vascular cells. L5, the most negatively charged subfraction of LDL, is an extreme form of electronegative LDL that we isolated through anion-exchange chromatograpgy in the plasma of patients with increased cardiac risks. L5, which is scant in healthy normal subjects, is as potent as artificially prepared oxLDL in inducing a spectrum of atherogenic responses in vascular cells. Most important, in patients recently admitted China Medical University Hospital (CMUH) in Taichung, we found marked increases in their plasma L5 concentration, which declined after percutaneous coronary intervention (PCI) and medical treatment. Intracoronary tissue removed by thrombectomy also revealed changes suggestive of L5 involvement. Based on these important findings, we are proposing a comprehensive study to determine the role of L5 in coronary plaque formation and destabilization in patients with acute coronary syndrome (ACS), in particular ST-elevation myocardial infarction (STEMI). The proposed study comprises 4 aims designed to address this imperative medical issue from clinical, chemical, cell/molecular, and histological aspects. In aim 1, we will investigate whether L5 is indeed significantly increased in the peri-MI periods and whether the variation of plasma L5 concentration after PCI treatment can be interpreted as evidence of its existence in the plaques. Aims 2 and 3 are designed to examine L5’s effect on selected mechanisms contributory to plaque pathology. Specifically, its effects on LDL aggregation, scavenger receptor induction in monocytes, gelatinase hyperactivity, and platelet activation/aggregation. Aim 4 is designed for extensive examination of the intracoronary tissue to identify L5’s involvement in clinical pathology. The study will be performed entirely at CMUH in Taiwan. The results will help disclose the mystery of a long lasting question that concerns the public health to the highest degree. The derived conclusions will also provide new clues and direction for further research designed for the development of targeted diagnostic and therapeutic methods with unprecedented accuracy. Because of undisputable importance of this matter, there is a true urgency for the proceeding of this project. Our goal is to be among the first to identify with confidence the culprit LDL entity responsible for ACS and, on that base, continue to lead research in this field that deals with major public health concern not only in Taiwan, but also in many other parts of the world.
顯示於類別:	[臨床醫學研究所] 研究計畫

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