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HDL, paraoxonase and atherosclerosis

HDL、对氧磷酶和动脉粥样硬化

基本信息

批准号：
12671101
负责人：
TSUKAMOTO Kazuhisa
金额：
$ 2.24万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671101/
关键词：
paraoxonase I HDL Apolpoprotein A-I oxidized lipia PAF-AH LDL macrophage atherosclerosis RAF-AH アポAI 酸化動脈硬化症

项目摘要

Paraoxonase 1 (PON1) is an enzyme that is associated with HDL and removes oxidized lipids from lipoproteins. In this study, we analyzed its property not only by utilizing the serum from an apoAI deficient patient but also by overexpressing PON1 protein using adenoviral-mediated gene transfer technique in mice. PON1 protein was exclusively distributed on HDL particles in apoAI deficiency, however, its stability in both the activity and localization on HDL was reduced in apoAI deficiency. Over-expression of PON1 protein in mice results in its exclusive association on HDL particles. HDL particles containing abundant PON1 protein were resistant to oxidative stress, and possessed not only protective function against foam cells formation from macrophages by oxidized LDL, but also enhancing effect for efflux of cholesterol from lipid-laden macrophages. We also evaluated the property of PAF-AH, an another lipoproteinassociated enzyme which possesses activity in catalyzing oxidized lipids as well as PON1. When over-expressed in mice, PAF-AH distributed not only on HDL particles but also on non-HDL particles. All of the lipoprotein particles abundant in PAF-AH were resistant to oxidative stress, and the HDL particles carrying excess PAF-AH possessed the same anti-atherogenic property on macrophages as was observed in HDL abundant in PON1.

对氧磷酶1(PON1)是一种与高密度脂蛋白相关的酶，能去除脂蛋白中的氧化脂质。在这项研究中，我们不仅利用ApoAI缺陷患者的血清，而且通过腺病毒介导的基因转移技术在小鼠中过表达PON1蛋白来分析其性质。在ApoAI缺乏时，PON1蛋白仅分布在高密度脂蛋白颗粒上，而在ApoAI缺乏时，PON1蛋白在高密度脂蛋白上的活性和定位的稳定性降低。PON1蛋白在小鼠体内的过度表达导致其与高密度脂蛋白颗粒的排他性结合。含有丰富PON1蛋白的高密度脂蛋白颗粒具有抗氧化应激作用，不仅对氧化低密度脂蛋白诱导的巨噬细胞形成泡沫细胞具有保护作用，而且对高脂巨噬细胞的胆固醇外流具有促进作用。我们还评估了另一种脂蛋白相关酶PAF-AH的性质，该酶与PON1一样具有催化氧化脂质的活性。当PAF-AH在小鼠体内过表达时，不仅分布在高密度脂蛋白颗粒上，也分布在非高密度脂蛋白颗粒上。所有富含PAF-AH的脂蛋白颗粒都能抵抗氧化应激，携带过量PAF-AH的高密度脂蛋白颗粒对巨噬细胞具有与富含PON1的高密度脂蛋白相同的抗动脉粥样硬化作用。