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

泡沫细胞被认为是黄斑瘤和动脉粥样硬化的特征性特征。早期动脉粥样硬化病变中的许多泡沫细胞具有单源性巨噬细胞的特征。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。一些研究人员在体外证明巨噬细胞可以通过受体介导的内吞作用摄取大量天然脂蛋白，如β - vldl、WHHL-VLDL和某些化学修饰的脂蛋白，如乙酰化LDL和丙二醛处理的LDL，从而成为泡沫细胞。然而，改性低密度脂蛋白尚未被证明存在于体内。据报道，最近氧化的LDL至少部分通过乙酰-LDL受体被噬体有效吸收。由于病理或流行病学调查表明脂质过氧化与动脉粥样硬化有关，氧化LDL被认为是自然发生的修饰LDL的一个候选例子。最近，我们利用whhl -兔（一种家族性高胆固醇血症动物模型）证明，普罗布考最初是作为一种抗氧化剂开发的，可在体内阻止动脉粥样硬化斑块的进展，这表明体内间接存在氧化的LDL。因此，在本研究中，我们研究了普罗布考的体外抗动脉粥样硬化的确切机制。首先，我们研究了普罗布考的抗氧化作用。与未经处理的whhl -兔分离的LDL相比，经probubl处理的whhl -兔分离的LDL显示出对铜离子氧化修饰的抗性，并且巨噬细胞对其的识别程度最低。在实验过程中，我们发现了氧化LDL的特异性受体的存在。我们现在正在提纯这个受体。probucol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LDL）的摄取，从而阻止巨噬细胞的泡沫细胞转化。因此，我们调查了这种可能性。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，它们会合成几种生物活性物质，如白细胞介素1、淀粉样代谢产物和MDGF。这些产品引起了越来越多的关注，因为最近的研究表明它们与动脉粥样硬化密切相关。因此，我们质疑普罗布考是否可以影响巨噬细胞形成这些产物，作为抗动脉粥样硬化的作用。然而，到目前为止，我们还不能在体外证明普罗布考的这种作用。少

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