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

泡沫细胞已被认为是黄瘤和动脉粥样瘤的特征。早期动脉粥样硬化病变中的许多泡沫细胞具有单一来源巨噬细胞的特征，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前体细胞。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，摄取大量的天然脂蛋白，如β-VLDL，WHHL-VLDL，以及某些化学修饰的脂蛋白，如乙酰化低密度脂蛋白和丙二醛处理的低密度脂蛋白，从而成为泡沫细胞。然而，还没有证据表明体内存在修饰的低密度脂蛋白。最近，据报道氧化的低密度脂蛋白被噬菌体有效地摄取，至少部分是通过乙酰化低密度脂蛋白受体。由于病理学或流行病学研究表明脂质过氧化与动脉粥样硬化的形成有关，氧化低密度脂蛋白被认为是…。更多的是一个自然发生的，修饰的低密度脂蛋白的例子。最近，使用WHHL-兔，一个家族性高胆固醇血症的缺氧模型，我们证明了普罗布考，最初是作为一种抗氧化剂开发的，可以防止体内动脉粥样斑块的进展，这间接地表明体内存在氧化的低密度脂蛋白。因此，在本研究中，我们对普罗布考的体外抗动脉粥样硬化作用机制进行了研究。首先，我们研究了普罗布考的抗氧化作用。经普罗布布利处理的WHHL兔的低密度脂蛋白能抵抗铜离子的氧化修饰，与未处理的WHHL兔的低密度脂蛋白相比，巨噬细胞对低密度脂蛋白的识别能力最低。在实验过程中，我们发现了氧化低密度脂蛋白的特异性受体的存在。我们现在正在做的是纯化这种受体。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的摄取，如β-极低密度脂蛋白、低密度脂蛋白、氧化低密度脂蛋白或香烟烟雾修饰的低密度脂蛋白，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。但普罗布考在体外不能阻止致动脉粥样硬化脂蛋白的摄取。当巨噬细胞成为泡沫细胞时，它们会合成几种生物活性物质，如白介素1、花生四烯酸代谢产物和MDGF。由于最近的研究表明它们与动脉粥样硬化的形成密切相关，这些产品引起了越来越多的关注。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，作为一种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。较少

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