ROLE OF MODIFIED LIPOPROTEINS AND THE IMMUNE SYSTEM IN ATHEROGENESIS

该股的总体目标是调查经修改的 脂蛋白和对这些修饰的免疫反应 动脉粥样硬化的动物模型。其中最引人注目的一句台词 支持氧化假说的证据之一是观察到 21项干预研究中有14项认为有效的亲脂性抗氧化剂， 如普罗布考，抑制动脉粥样硬化的进展 动物模型。然而，在5项研究中，包括我们的两项研究 实验室发现，抗氧化剂对低密度脂蛋白的保护作用较小 而不是减少动脉粥样硬化的形成。本单元的一个主要目标是了解 这些例外情况。具体地说，我们将测试以下假设： 在给定氧化应激程度的情况下， 必须达到低密度脂蛋白以减少动脉粥样硬化的形成，而且 阈值取决于高胆固醇血症的程度。这 假说将被检验以确定一种抗动脉粥样硬化的作用。 天然和合成脂类抗氧化剂在低密度脂蛋白中的组合 不同水平饮食诱导的受体缺陷(LDLR-/-)小鼠 高胆固醇血症。相反，抗动脉粥样硬化的作用 越来越有效的抗氧化剂，或抗氧化剂的组合， 将在恒定的血浆胆固醇水平下进行测试。知识 这一假设是正确的，这在设计中将是重要的 人体临床试验。该股的第二个目标是测试 假设低密度脂蛋白的氧化修饰和 晚期糖基化终末产物(AGE)的产生 非酶糖基化是相辅相成的，会导致动脉粥样硬化 流程。这将通过对正常血糖的干预研究来检验。 LDLR-/-兔子和小鼠，我们已经证明它们包含两种年龄 和OxLDL在动脉粥样硬化病变中的表达。我们将确定是否 抗氧化剂，或抗氧化剂和氨基胍的组合， 可以抑制AGE和OxLDL的形成。最后，本单位 将探索观察到的氧化低密度脂蛋白的后果 具有很强的免疫原性。我们将检验这一假设 增强对氧化脂蛋白的免疫反应将在 转而调节病变的形成。我们之前已经证明了 氧化型低密度脂蛋白表位免疫WHHL兔的实验研究 减少动脉粥样硬化。我们现在将确定是否会产生类似的影响 在LDLR-/-和apoE缺陷小鼠中发生 OxLDL的表位，并将确定最佳的免疫原和 抑制动脉粥样硬化的免疫方案。我们还将 利用apaE缺陷小鼠或LDLR-/-小鼠的杂交和免疫- 以确定免疫接种的机制 抑制动脉粥样硬化的形成过程。总而言之，该股将 研究多种抗氧化剂的抗氧化性和免疫力 减少动脉粥样硬化形成的干预措施。所获得的信息 不仅应该提供对基本的动脉粥样硬化形成机制的洞察， 但也可以提供有用的信息，指出有效和 新的治疗策略。

The overall aim of this Unit is to investigate the role of modified lipoproteins and the immune response to these modifications in animal models of atherosclerosis. One of the most compelling lines of evidence supporting the oxidation hypothesis is the observation in 14 of 21 intervention studies that potent lipophilic antioxidants, such as probucol, inhibit the progression of atherosclerosis in animal models. However, in 5 studies, including two from our laboratory, antioxidants which provided less protection to LDL did not reduce atherogenesis. A major goal of this unit is to understand these exceptions. Specifically, we will test the hypothesis that for a given degree of oxidative stress a threshold level of protection for LDL must be achieved to reduce atherogenesis and that the threshold depends on the degrees of hypercholesterolemia. This hypothesis will be tested determining the antiatherogenic effect of a combination of natural and synthetic lipophilic antioxidants in LDL receptor-deficient (LDLR-/-) mice at different levels of diet-induced hypercholesterolemia. Conversely, the antiatherogenic effect of increasingly potent antioxidants, or combinations of antioxidants, will be tested at a constant level of plasma cholesterol. Knowledge that this hypothesis is correct would be important in designing clinical trials in man. The second aim of this Unit is to test the hypothesis that the oxidative modification of LDL and the generation of advanced glycation end products (AGE) by nonenzymatic glycation are mutually reinforcing, proatherogenic processes. This will be tested by intervention studies in euglycemic LDLR-/- rabbits and mice, which we have shown contain both AGE and OxLDL in atherosclerotic lesions. We will determine if antioxidants, or combinations of antioxidants and aminoguanidine, can inhibit both AGE and OxLDL formation. Finally, this Unit will explore the consequences of the observation that oxidized LDL is highly immunogenic. We will test the hypothesis that augmentation of immune responses to oxidized lipoproteins will in turn modulate lesion formation. We previously showed that hyperimmunization of WHHL rabbits with epitopes of OxLDL reduced atherosclerosis. We will now determine if a similar effect occurs in LDLR-/- and apoE-deficient mice immunized with epitopes of OxLDL, and will determine optimal immunogens and immunization regimens to inhibit atherosclerosis. We will also utilize hybrids of apaE-deficient or LDLR-/- mice and immune- deficient mice to determine the mechanisms by which immunization inhibits the atherogenic process. In summary, this Unit will investigate the ability of a variety of antioxidant and immunological interventions to reduce atherogenesis. The information gained should not only provide insight into basic atherogenic mechanisms, but may also provide useful information pointing to effective and novel therapeutic strategies.