ROLE OF MODIFIED LIPOPROTEINS AND THE IMMUNE SYSTEM IN ATHEROGENESIS

本单位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。最引人注目的一句话 支持氧化假说的证据之一是观察到， 21项干预研究中有14项表明， 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， 在实验室中，对LDL提供较少保护的抗氧化剂 而不是减少动脉粥样硬化形成。 本单元的一个主要目标是了解 这些例外。 具体地说，我们将测试假设， 给定氧化应激的程度， 必须达到低密度脂蛋白，以减少动脉粥样硬化形成， 阈值取决于高胆固醇血症的程度。 这 假设将被测试，以确定抗动脉粥样硬化的效果， LDL中天然和合成亲脂性抗氧化剂的组合 受体缺陷（LDLR-/-）小鼠在不同水平的饮食诱导 高胆固醇血症 相反， 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， 本单位的第二个目的是测试 假设LDL的氧化修饰和 晚期糖基化终产物（AGE）的产生， 非酶糖基化是相互加强的，促动脉粥样硬化的 流程.这将通过血糖正常的干预研究来检验。 LDLR-/-兔和小鼠，我们已经证明， 和氧化低密度脂蛋白。我们将确定是否 抗氧化剂，或抗氧化剂和氨基胍的组合， 能抑制AGE和OxLDL的形成。 最后，本单位 将探讨氧化低密度脂蛋白 具有高度免疫原性。 我们将检验这个假设， 增强对氧化脂蛋白的免疫反应将 转动调节损伤形成。 我们之前已经证明， 氧化低密度脂蛋白表位超免疫WHHL兔 减少动脉粥样硬化。 我们现在将确定是否有类似的效果 在LDLR-/-和apoE缺陷小鼠中发生， 表位的OxLDL，并将确定最佳的免疫原， 免疫方案来抑制动脉粥样硬化。 我们还将 利用apaE缺陷或LDLR-/-小鼠和免疫- 缺陷小鼠，以确定免疫的机制， 抑制动脉粥样硬化过程。 总之，该股将 考察了多种抗氧化剂和免疫学能力 减少动脉粥样硬化形成的干预措施。 获得的信息 不仅能提供对基本动脉粥样硬化机制的深入了解， 而且还可以提供有用的信息， 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.