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題名 | Risk Factors, Endothelial Cell Turnover and Lipid Transport in Atherogenesis==危險因子、內皮細胞週轉與動脈硬化生成過程中脂質輸送的關係 |
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作者 | 林幸榮; Lin, Shing-jong; |
期刊 | 中華醫學雜誌 |
出版日期 | 19961100 |
卷期 | 58:5 1996.11[民85.11] |
頁次 | 頁309-316 |
分類號 | 415.384 |
語文 | eng |
關鍵詞 | 動脈硬化症; 細胞週轉; 內皮細胞; 細胞接合處; 通透性; 危險因子; Atherosclerosis; Cell turnover; Endothelium; Intercellular junction; Permeability; Risk factor; |
中文摘要 | 心臟血管疾病近年來仍然高居台灣地區十大死因的第四位,動脈粥狀 硬化症和冠狀動脈疾病經常引起心肌梗塞和心臟衰竭的發生,是導致死亡最主 要的原因。動脈硬化病變最明顯的特徵之一,就是局部血管壁的脂肪堆積,主 要是以膽固醇酯或游離膽固醇的型式堆積在細胞內或細胞外間質中。重覆性的 內皮細胞損傷和增加脂肪浸潤是形成動脈硬化的關鍵性過程。血中的脂蛋白可 以經由囊泡輸送系統直接穿越內皮細胞或經由細胞間之接合處穿過內皮細胞層 而進入血管壁中。我們以往的研究已顯示大部分的動脈內皮細胞分裂會伴隨白 蛋白和低密度脂蛋白的洩漏,後續的研究亦發現內皮細胞的死亡也伴隨有穿內 皮細胞層大分子物質的洩漏,這些發現說明當內皮細胞進行週轉時所發生的暫 時性易漏細胞接合處可以提供重要的途徑,增加大分子物質包括低密度脂蛋白 的輸送穿過內皮細胞層。電子顯微鏡研究亦顯示內皮細胞分裂時其細胞接合處 呈現明顯變寬現象,提供了直接證據支持導致動脈硬化生成局部化之”細胞週 轉一易漏接合處”理論。 高血壓、抽菸、糖尿病和高脂血症是眾所週知導致動脈硬化症和冠狀動脈 心臟症的主要危險因子。在一系列的研究中,我們測試這樣的假說:高血壓、 抽菸、糖尿病和高脂血症會增加動脈內皮細胞的週轉率,因此加強穿內皮細胞 層大分子物質的輸送,增加脂肪進入血管壁中而加速動脈硬化的生成。 我們在成年雄性自發性高血壓老鼠(SHR)、Wistar-Kyoto (WKY)正常血壓老 鼠和Sprague-Dawley (SD)老鼠進行動物實驗。SHR做為高血壓動物組而WKY老 鼠做為正常血壓對照組;SD老鼠飲用含尼古丁的水(每天每公斤體重5毫克) 長達6週來仿效抽菸的效應;在SD老鼠腹腔內單一注射streptozotocin(每公斤 體重60毫克)來誘導糖尿病產生並持續期間長達6週;另外一批SD老鼠則餵 食含5%膽固醇飼料來誘發高脂血症,期間亦達6週之久。每一實驗組動物都有 相對應的對照組做比較。在胸主動脈的正面標本上利用蘇木素染色法來找出分 裂中的內皮細胞,另外以間接免疫細胞化學法來找出死亡的內皮細胞,還有利 用螢光顯微鏡檢術來觀察和定量內皮細胞層對於大分子物質(EBA)的洩漏。 結果顯示:和正常對照老鼠比較,自發性高血壓老鼠、慢性飲用含尼古丁 水的老鼠、糖尿病老鼠還有高脂血症老鼠等在主動脈中都有較高的內皮細胞死 亡頻率和大分子物質的洩漏,這些發現說明高血壓、抽菸、糖尿病和高脂血症 等之所以會成為動脈硬化生成的主要危險因子,乃是經由增加內皮細胞的週轉 率和伴隨的內皮細胞層通透性,增強易致動脈硬化的脂蛋白進入血管壁中,進 而加速動脈硬化的形成。 |
英文摘要 | Cardiovascular diseases remain to be the 4th rank of top ten causes of mortality in Taiwan in recent years. Atherosclerosis and coronary artery disease, which often culminating in the occurrence of myocardial infarction and congestive heart failure, are responsible for the majority of these death. One of the prominent features of atherosclerotic lesion is local accumulation of lipids, mainly in the forms of cholesteryl ester and free cholesterol, either within cells or extracellularly in matrix. Repeated endothelial injury and enhanced lipid infiltration are critical events in the development of atherosclerosis. Plasma lipoproteins may enter the arterial wall through endothelium, either transcellularly via vesicular transport or paracellularly via intercellular junction. Our previous studies have demonstrated that most of the arterial endothelial cells in mitosis are associated with the leakage of fluorescently labeled albumin and low density lipoproteins. Subsequently, such transendothelial leakage of macromolecules is also shown to be associated with endothelial cell death as assessed by immunocytochemical staining for IgG. These findings suggested that transiently leaky junctions occurring during endothelial cell turnover may provide potentially important pathways for increasing transport or leakage of macromolecules, including atherogenic LDL, across the vascular endothelium. Electron microscopic study using horseradish peroxidase as a tracer revealed markedly widening of intercellular junctions around endothelial cells in mitosis providing direct evidence in support of "cell turnover-leaky junction" theory for the localization of atherogenesis. Hypertension, smoking, diabetes, and hyperlipidemia are well-known major risk factors for atherosclerosis and coronary heart disease. In a series of investigations, we examined the hypothesis that hypertension smoking, diabetes, and hyperlipidemia increase the arterial endothelial cell turnover and hence transendothelial macromolecular transport, which may have some implications in increasing lipid entry and thus, accelerating atherogenesis. Animal experiments were performed in adult male spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) normotensive rats, and Sprague-Dawley (SD) rats. SHRs were used as hypertensive group with WKY rats as normotensive control. SD rats were given nicotine at a dose of 5 mg/Kg body wt/day in their drinking water to mimic smoking effect over a period of 6 weeks. Diabetes was induced in SD rats by single intraperitoneal injection of 60 mg/Kg body wt of streptozotocin. The duration of diabetes was 6 weeks. Also, SD rats were fed a diet containing 5% cholesterol for 6 weeks to induce hyperlipidemia. Age-matched rats of comparable number served as control for each experimental group. In en face preparations of thoracic aorta, mitotic endothelial cells were identified by hematoxylin staining, immunoglobulin G-containing dying or dead endothelial cells were detected by an indirect immunoperoxidase method, and endothelial leakage to Evans blue- albumin (EBA) complexes (5 minutes after intravenous injection) was visualized and quantified by fluorescence microscopy. The results showed that SHR, chronic oral nicotine-treated rats, diabetic rats, and hyperlipidemic rats, when compared to control rats, had higher values for the frequency of endothelial cell death and the number density of EBA leaky foci in the aorta. These findings suggested that hypertension, cigarette smoking, diabetes mellitus, and hyperlipidemia become risk factors in atherogenesis by increasing the rate of arterial endothelial cell turnover and the associated endothelial permeability, leading to the consequent enhanced entry of atherogenic lipoproteins into the arterial wall and accelerated atherogenesis. |
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