Modulators of HDL Structure-Function

许多人口和动物研究已经建立了高密度的动脉粥样硬化保护性能， 脂蛋白（HDL）。除了从外周血中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进行排泄（胆固醇逆向转运，RCT），HDL还具有 抗炎和抗氧化特性。HDL治疗领域的一个新兴领域是 载脂蛋白模拟肽的开发。我们已经表明，口服给药的apoA-l-模拟物 肽导致动脉粥样硬化敏感性 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 具有增加的帕氧磷酶-1（PON 1）活性的能够破坏脂质的prep-HDL样颗粒 氢过氧化物（LOOH）和增强胆固醇逆向转运，主要抗动脉粥样硬化特性， 载脂蛋白A-1因此，抗动脉粥样硬化肽调节HDL的性质，使得促动脉粥样硬化HDL被抑制。 转化为抗动脉粥样硬化的HDL。我们提出了两种抗动脉粥样硬化的形成机制， a和preJBHDL在抗动脉粥样硬化肽存在下的相互作用：1）增强与ABCA 1的相互作用，以形成 仅含有载脂蛋白A-1的颗粒的水平增加，前β-HDL的PON 1水平的量增加 2）增强α-HDL颗粒的受体（SRB-1）相互作用以清除胆固醇酯，因此 再生活性前β-HDL颗粒。我们假设抗动脉粥样硬化的特性是由 肽（肽-脂质复合物）募集apoA-1、LOOH和酶如PON 1的能力 存在于HDL中。例如，如果PON 1在这些颗粒上没有活性，则这种HDL是炎症性的，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：1a。肽的影响 HDL的组成结构。1b.肽缔合的结构方面; 2a.抗动脉粥样硬化 每种肽的潜力。2b.测试所选肽的抗动脉粥样硬化性质， 动脉粥样硬化敏感小鼠模型。我们将使用物理的，物理化学的，体外细胞培养， 在动脉粥样硬化动物模型中的体内研究，以表征肽介导的 与抗动脉粥样硬化特性相关的HDL变化。这些研究将首次 使我们能够了解肽调节的抗动脉粥样硬化HDL的详细结构， apoA-I-模拟肽的抗动脉粥样硬化和抗炎作用的机制。而且这些 研究将导致设计简单的分子， 并可能导致改善动脉粥样硬化的新模式。

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.