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The role of endothelial lipase in pathogenesis of atherosclerosis : A novel therapeutic target for raising HDL cholesterol

内皮脂肪酶在动脉粥样硬化发病机制中的作用：提高高密度脂蛋白胆固醇的新治疗靶点

基本信息

批准号：
16390226
负责人：
YOKOYAMA Mitsuhiro
金额：
$ 9.02万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Recently, we have cloned endothelial cell-derived lipase (EL), a new member of the lipase gene family, from endothelial cells during vascular formation. To investigate role of EL in lipoprotein metabolism and atherosclerosis, we generated transgenic and knockout mice of EL, and analyzed the lipid profiles. Characterization of EL transgenic and knockout mice revealed that EL expression correlates inversely with circulating HDL-C levels in genetic mouse models. To investigate the role of EL in atherosclerotic progression, apoE/EL double knockout mice were generated and analyzed. Atherosclerotic lesion area was decreased by 70% in the EL/apoE double knockout mice compared with the apoE single knockout mice. Despite the increase in plasma cholesterol, EL/apoE double knockout mice showed significantly decreased aortic plaque sizes. EL may have atherogenic actions in vivo through its effect on circulating HDL cholesterol and non-enzymatic bridging function. EL mRNA was upregulated in endothelial cells by inflammatory cytokines implicated in vascular disease etiology, including TNF-α and IL-1β. Immunohistochemical analysis revealed that EL was expressed in endothelial and smooth muscle cells, as well as infiltrating cells, in the atheromatous plaque in human coronary arteries. In EL knockout mice, acute inflammatory reaction by LPS injection did not affects the HDL-C levels, although HDL-C was reduced by LPS injection in control wild type mice. Thus, upregulation of EL may account for the reduced HDL-C in systemic inflammation. Taken together presence of EL and regulated expression of EL may have unique functional roles in the pathogenesis of coronary artery diseases such as atherosclerosis as well as in lipid metabolism in the vessel wall. Therefore, EL is considered to be an attractive therapeutic target for pharmacological intervention to raising HDL-C and to prevent atherosclerosis.

最近，我们从血管形成过程中的内皮细胞克隆了内皮细胞衍生脂肪酶(EL)，这是脂肪酶基因家族中的一个新成员。为了研究EL在脂蛋白代谢和动脉粥样硬化中的作用，我们建立了EL的转基因和基因敲除小鼠，并对其进行了脂谱分析。对EL转基因和基因敲除小鼠的研究表明，在遗传小鼠模型中，EL的表达与循环中的高密度脂蛋白胆固醇水平呈负相关。为了探讨EL在动脉粥样硬化进展中的作用，建立了apoE/EL双基因敲除小鼠，并对其进行了分析。EL/apoE双基因敲除小鼠的动脉粥样硬化病变面积较apoE单基因敲除小鼠减少70%。尽管血浆胆固醇增加，EL/apoE双基因敲除小鼠的主动脉斑块大小显著减少。EL可能通过影响循环中的高密度脂蛋白胆固醇和非酶桥功能而在体内发挥致动脉粥样硬化作用。与血管疾病相关的炎性细胞因子，包括肿瘤坏死因子-α和白介素1-β，上调了血管内皮细胞中EL基因的表达。免疫组织化学分析显示，EL表达于人冠状动脉内皮细胞、平滑肌细胞以及动脉粥样硬化斑块中的浸润性细胞。在EL基因敲除小鼠，注射脂多糖引起的急性炎症反应不影响高密度脂蛋白胆固醇水平，而对照野生型小鼠注射脂多糖可降低高密度脂蛋白胆固醇水平。因此，EL的上调可能是全身炎症中高密度脂蛋白胆固醇降低的原因。综上所述，EL的存在和EL的调节表达可能在动脉粥样硬化等冠状动脉疾病的发病机制以及血管壁脂代谢中具有独特的功能作用。因此，EL被认为是药物干预升高高密度脂蛋白胆固醇和预防动脉粥样硬化的一个有吸引力的治疗靶点。