Impact of Oxidative Modification on HDL Function

氧化修饰对 HDL 功能的影响

• 批准号: 9353659
• 负责人: Rebecca L. Schill
• 金额: $ 2.69万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353659
• 关键词: 4 hydroxynonenal; Acrolein; Aldehydes; Alpha Particles; Antiatherogenic; Arteries; Atherosclerosis; Biology; Blood Circulation; Cardiovascular Diseases; Cholesterol; Cholesterol Esters; Chronic; Data; Development; Diagnostic; Environmental Risk Factor; Excretory function; Exposure to; Foam Cells; Future; Genes; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Impairment; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Lead; Lesion; Light; Lipid Peroxidation; Lipid Peroxides; Lipids; Lipoproteins; Measures; Mediating; Modeling; Modification; Mus; Mutation; Outcome Study; Oxidative Stress; Oxides; Pathway interactions; Patients; Peritoneal Macrophages; Physiological; Process; Property; Research; Risk; Role; Signal Transduction; Stress; Testing; Therapeutic; Time; atherogenesis; base; cardiovascular disorder prevention; cardiovascular disorder risk; cigarette smoking; clinical development; clinical diagnostics; combat; cytokine; design; experimental study; high density lipoprotein receptor; in vivo; insight; low density lipoprotein inhibitor; macrophage; migration; novel; novel therapeutic intervention; oxidized LDL receptors; oxidized low density lipoprotein; particle; prevent; therapeutic target

PROJECT SUMMARY High circulating levels of high-density lipoprotein (HDL)-cholesterol (HDL-C) have been correlated with a decreased risk in cardiovascular disease (CVD). However, recent studies have demonstrated that HDL function, and not HDL-C levels, may be a more important indicator for CVD risk. During times of chronic inflammation and/or prolonged circulation, HDL is susceptible to oxidative modification. The long-term goal of these studies is to better understand how oxidative modification to HDL compromises its anti-atherogenic functions and generates a pro-atherogenic particle. Our preliminary data indicate that oxidative modification of HDL by either acrolein (acro; major component of cigarette smoke) or 4-hydroxynoneal (HNE; product of lipid peroxidation) results in impaired cholesterol transport functions. Based on these data, we have designed experiments to test the overall hypothesis that oxidized forms of HDL promote pathways that lead to atherogenesis. In Aim 1, we hypothesize that modification of HDL with HNE- and/or acrolein generates a particle that has pro-atherogenic effects on macrophages. We will determine whether acro- and/or HNE- modified HDL can induce the expression of pro-inflammatory cytokines in macrophages, similar to oxidized LDL (oxLDL). Further, we will also determine whether our modified forms of HDL can inhibit macrophage migration. In Aim 2, we will determine if the oxLDL receptor, CD36, can also function as a dysfunctional HDL receptor in macrophages. First, we will test the hypothesis that cholesteryl ester (CE) delivery from oxidized forms of HDL to macrophages is mediated by CD36. Second, we will determine whether acro- and/or HNE- modified HDL can induce CD36-mediated signaling cascades. In Aim 3, we hypothesize that SR-BI deficiency, a model of high HDL-C and impaired clearance of HDL-C due to lack of the HDL receptor, produces dysfunctional HDL particles in vivo. In order to test this novel hypothesis, we will first determine whether HDL isolated from SR-BI-null mice contains oxidative modifications. Next, we will test whether HDL from SR-BI-null mice promotes accumulation of cholesterol in macrophages, and induces pro-inflammatory responses while inhibiting macrophage migration. Together, these studies will shed light on how oxidative modifications to HDL can promote pathways that lead to atherogenesis. We anticipate that the findings from our studies will provide novel insight towards understanding the complexity of HDL function, and may lead to the identification of potential therapeutic targets to combat atherosclerosis.

项目概要 高循环水平的高密度脂蛋白 (HDL)-胆固醇 (HDL-C) 与 降低心血管疾病（CVD）的风险。然而，最近的研究表明 HDL 功能而不是 HDL-C 水平可能是 CVD 风险更重要的指标。在慢性病时期 炎症和/或延长循环，HDL 容易受到氧化修饰。长期目标是 这些研究是为了更好地了解 HDL 的氧化修饰如何损害其抗动脉粥样硬化作用 发挥作用并产生促动脉粥样硬化颗粒。我们的初步数据表明，氧化修饰 HDL 由丙烯醛（acro；香烟烟雾的主要成分）或 4-羟基壬醛（HNE；脂质产物 过氧化）导致胆固醇转运功能受损。根据这些数据，我们设计了 实验检验总体假设，即 HDL 的氧化形式促进导致 动脉粥样硬化。在目标 1 中，我们假设用 HNE-和/或丙烯醛修饰 HDL 会产生 对巨噬细胞具有促动脉粥样硬化作用的颗粒。我们将确定是否 acro- 和/或 HNE- 修饰的 HDL 可以诱导巨噬细胞中促炎细胞因子的表达，类似于氧化的 HDL 低密度脂蛋白（oxLDL）。此外，我们还将确定我们的 HDL 修饰形式是否可以抑制巨噬细胞 迁移。在目标 2 中，我们将确定 oxLDL 受体 CD36 是否也可以充当功能失调的 HDL 巨噬细胞中的受体。首先，我们将检验以下假设：胆固醇酯 (CE) 从氧化 HDL 形式向巨噬细胞的传递是由 CD36 介导的。其次，我们将确定 acro- 和/或 HNE- 修饰的 HDL 可以诱导 CD36 介导的信号级联反应。在目标 3 中，我们假设 SR-BI 缺乏， 由于缺乏 HDL 受体而导致高 HDL-C 和 HDL-C 清除受损的模型，产生 体内 HDL 颗粒功能失调。为了检验这个新假设，我们首先确定 HDL 是否 从 SR-BI 缺失小鼠中分离出的含有氧化修饰的物质。接下来，我们将测试HDL是否来自SR-BI-null 小鼠促进巨噬细胞中胆固醇的积累，并诱导促炎症反应，同时 抑制巨噬细胞迁移。总之，这些研究将揭示 HDL 的氧化修饰如何 可以促进导致动脉粥样硬化形成的途径。我们预计我们的研究结果将提供 理解 HDL 功能复杂性的新见解，并可能导致识别 对抗动脉粥样硬化的潜在治疗靶点。