Modulators of HDL Structure-Function

大量的人群和动物研究已经确定了高密度的动脉粥样硬化保护特性 脂蛋白(Hdl)。除了从外周提取胆固醇的主要抗动脉粥样硬化特性外 细胞并将其转移到肝脏排泄(反向胆固醇运输，RCT)，高密度脂蛋白还拥有 抗炎和抗氧化性能。高密度脂蛋白治疗领域的一个新兴领域是 载脂蛋白模拟肽的研究进展。我们已经证明，口服载脂蛋白A-L-模拟物 多肽显著减少动脉粥样硬化敏感者动脉粥样硬化病变的形成 小鼠模型，尽管胆固醇水平没有变化。我们假设这是通过形成 具有增强的对氧磷脂酶-1(PON1)活性的PREP-HDL样颗粒，能够破坏脂质 过氧化氢(LOOH)和促进胆固醇逆向转运，其主要抗动脉粥样硬化特性 阿波亚-L。因此，抗动脉粥样硬化多肽调节高密度脂蛋白的性质，从而使致动脉粥样硬化的高密度脂蛋白 转化为抗动脉粥样硬化的高密度脂蛋白。我们提出了两种形成抗动脉粥样硬化的机制 在抗动脉粥样硬化多肽存在下的A和前JBHDL1：1)增强与ABCA1的相互作用形成 随着前(3-高密度脂蛋白)水平的增加，仅含载脂蛋白A-L的颗粒水平增加 颗粒；以及2)α-高密度脂蛋白颗粒的增强受体(SRB-1)相互作用以清除胆固醇酯，从而 再生活性Pre(3-高密度脂蛋白颗粒。我们假设抗动脉粥样硬化的特性是由 肽(肽-脂复合体)募集载脂蛋白A-L、LOOH和PON1等酶的能力 以高密度脂蛋白表示。例如，如果PON1在这些颗粒上不活跃，这种高密度脂蛋白是炎症的，因为它 拥有LOOH。为了检验我们的假设，我们提出了以下具体目标：多肽的影响 结构上的高密度脂蛋白的组成。1B.多肽缔合的结构方面；2a。抗动脉粥样硬化 每种多肽的潜力。2B。对选定的多肽进行抗动脉粥样硬化性能的测试 动脉粥样硬化敏感小鼠模型。我们将使用物理、物理化学、体外细胞培养和 多肽在动脉粥样硬化动物模型中的结构和功能研究 与抗动脉粥样硬化特性有关的高密度脂蛋白变化。这些研究将是第一次 使我们能够理解多肽调节的抗动脉粥样硬化高密度脂蛋白的详细结构方面以及 载脂蛋白A-L模拟肽的抗动脉粥样硬化和抗炎作用机制。此外，这些 研究将导致设计具有更强的抗动脉粥样硬化和抗炎作用的简单分子 并有可能导致新的方法来改善动脉粥样硬化。

Numerous population and animal studies have established the atheroprotective properties of high density lipoproteins (HDL). In addition to its main antiatherogenic property of extracting cholesterol from peripheral cells and transferring it to the liver for excretion (reverse cholesterol transport, RCT), HDL also possesses anti-inflammatory and antioxidant properties. An emerging area in the field of HDL therapy is the development of apolipoprotein mimetic peptides. We have shown that orally administered apoA-l-mimetic peptides result in a dramatic reduction in the atherosclerotic lesion formation in atherosclerosis-sensitive mouse models despite no change in cholesterol levels. We hypothesize that this occurs via the formation of prep-HDL-like particles that possess increased paroxonase-1 (PON1) activity which are able to destroy lipid hydroperoxides (LOOH) and enhance reverse cholesterol transport, the major antiatherogenic properties of apoA-l. Thus antiatherogenic peptides modulate the properties of HDL such that proatherogenic HDL is converted into antiatherogenic HDL. We propose two mechanisms for the formation of both antiatherogenic a and preJBHDL in the presence of antiatherogenic peptides: 1) enhanced interaction with ABCA1 to form increased levels of apo A-l-only containing particle with increased amounts of PON1 levels of pre(3-HDL particles; and 2) enhanced receptor (SRB-1) interaction of a-HDL particles to clear cholesteryl ester, thus regenerating active pre(3-HDL particles. We hypothesize that the antiatherogenic properties are governed by the ability of the peptide (peptide-lipid complexes) to recruit apoA-l, LOOH, and enzymes such as PON1 present in HDL. If, for example, PON1 is not active on these particles, this HDL is inflammatory since it possesses LOOH. To test our hypothesis we propose the following specific aims: 1a. Influence of peptide structure on the composition of HDL. 1b. Structural aspects of peptide association; 2a. Antiatherogenic potential of each peptide. 2b. Testing of selected peptides for their antiatherogenic properties in atherosclerosis sensitive mouse models. We will use physical, physico-chemical, in vitro cell culture and in vivo studies in animal models of atherosclerosis to characterize the structure and function of peptidemediated HDL changes that are related to antiatherogenic properties. These studies will for the first time enable us to understand the detailed structural aspects of peptide-modulated antiatherogenic HDL and the mechanism of antiatherogenic and anti-inflammatory actions of apoA-l-mimetic peptides. Furthermore, these studies will lead to the design of simple molecules with increased antiatherogenic and anti-inflammatory potencies and potentially lead to novel modalities to ameliorate atherosclerosis.