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Study for the initial events of atherosclerosis in WHHL-rabbit and its prevention.

WHHL兔动脉粥样硬化起始事件及其预防的研究。

基本信息

批准号：
63480270
负责人：
KITA Toru
金额：
$ 3.84万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

项目摘要

The foam cell has been recognized as characteristic feature of xanthomas and atheroma. Many foam cells in early atheromatous lesions share properties characteristic of the monocute derived macrophages.Rherefore, the macrophage may be the progenitor of certain foam cells that are involved in atherosclerosis. Several investigators demonstrated in vitro that macrophages can ingest large amounts of native lipoproteins, such as beta-VLDL, WHHL-VLDL and also the certain chemically modified lipoproteins, such as acetylated LDL and malondialdehyde-treated LDL through the process of receptor mediated endocytosis and thereby they become foam cells. Yet modified LDL has, not been demonstrated to exist in the body. Recently oxidized LDL has been reported to be efficiently taken up by marophages at least in part by way of acetyl-LDL receptor. Because lipid peroxidation has been suggested to be involved in atherogenesis by pathological or epidemiological investigation, oxidized LDL is considered as … More a candidate for an example of naturally occurring, modified LDL.Recently using WHHL-rabbit, an aniihal model for familial hypercholestrolemia, we demonstrated that probucol, originally developed as an antioxidant, prevents the progression of atheromatous plaques in vivo, suggesting the existence of oxidized LDL in vivo indirectly. Therefore in this study, we investigated the precise antialtherogenoc mechanisms of probucol in vitro. First, we studied antioxidant effects of probucol. LDL isolated from WHHL-rabbit under treatment with probucbl were shown to be resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages in comparison with LDL isolated from untreated WHHL-rabbits. In the middle of experiments, we discovered the existence of specific receptor for oxidized LDL. We are now doing to purify this receptor. There is a possibility that probucol might affect the membrane of macrophage to inhibit the uptake of atherogenic lipoproteins such as beta-VLDL, acety-LDL, oxidized LDL, or cigarette smoke modified LDL, subsequently preventing the foam cell transformation of macrophages. Therefore we investigated such a possibility. However, probucol could not prevent the uptake of atherogenic lipoproteins in vitro. When macrophages become foam cells, they synthesizes several biologically active substances, such as interleukin 1, araclidonate metabolites and MDGF. These products have attracted increasing attention, since recent studies have indicated their close relation to atherogenesis. Therefore we questioned whether probucol could affect the formation of these products by macrophages, as an antiatherogenic effect. However, so far, we could not demonstrated such an effect of probucol in vitro. Less

泡沫细胞已被认为是黄色瘤和动脉粥样硬化的特征。早期动脉粥样硬化病变中的许多泡沫细胞具有单核细胞衍生的巨噬细胞的特性，因此，巨噬细胞可能是参与动脉粥样硬化的某些泡沫细胞的祖细胞。一些研究者在体外证明，巨噬细胞可以通过受体介导的内吞过程摄取大量天然脂蛋白，如β-VLDL、WHHL-VLDL以及某些化学修饰的脂蛋白，如乙酰化LDL和丙二醛处理的LDL，从而它们成为泡沫细胞。然而，修饰的LDL尚未被证明存在于体内。最近已报道氧化的LDL至少部分通过乙酰基-LDL受体被噬菌体有效摄取。由于病理学或流行病学研究表明脂质过氧化作用参与动脉粥样硬化形成，因此氧化LDL被认为是动脉粥样硬化的一个重要因素。 ...更多信息最近，我们使用WHHL-兔，一种家族性高胆固醇血症的动物模型，证明了最初作为抗氧化剂开发的普罗布考在体内阻止动脉粥样硬化斑块的进展，间接地表明氧化LDL在体内的存在。因此，在本研究中，我们研究了普罗布考在体外的确切抗altherogenoc机制。首先，我们研究了普罗布考的抗氧化作用。与从未处理的WHHL-兔分离的LDL相比，在用probucbl处理下从WHHL-兔分离的LDL显示出对铜离子的氧化修饰具有抗性，并且被巨噬细胞最低限度地识别。在实验过程中，我们发现了氧化LDL的特异性受体的存在。我们现在正在纯化这种受体。普罗布考可能影响巨噬细胞膜，抑制致动脉粥样硬化脂蛋白如β-VLDL、乙酰-LDL、氧化LDL或香烟烟雾修饰的LDL的摄取，从而阻止巨噬细胞的泡沫细胞转化。因此，我们研究了这种可能性。然而，普罗布考在体外不能阻止致动脉粥样硬化脂蛋白的摄取。当巨噬细胞变成泡沫细胞时，它们合成几种生物活性物质，如白细胞介素1、花生四烯酸代谢物和MDGF。近年来的研究表明，这些产品与动脉粥样硬化的发生密切相关，因此引起了人们越来越多的关注。因此，我们怀疑普罗布考是否能影响巨噬细胞形成这些产物，作为一种抗动脉粥样硬化作用。然而，到目前为止，我们不能证明普罗布考在体外的这种作用。少