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.

项目摘要 高密度脂蛋白（HDL）-胆固醇（HDL-C）的高循环水平与 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风险的更重要指标。在慢性病时期， 炎症和/或循环延长，HDL易受氧化修饰。的长期目标 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， 起作用并产生促动脉粥样硬化颗粒。我们的初步数据表明， 通过丙烯醛（香烟烟雾的主要成分）或4-羟基壬醛（HNE;脂质的产物） 过氧化作用）导致胆固醇转运功能受损。根据这些数据，我们设计了 实验来测试的总体假设，氧化形式的HDL促进途径，导致 动脉粥样硬化在目的1中，我们假设用HNE-和/或丙烯醛修饰HDL产生了一种新的高密度脂蛋白。 对巨噬细胞具有促动脉粥样硬化作用的颗粒。我们将决定是否acro-和/或HNE- 修饰的HDL可诱导巨噬细胞表达促炎细胞因子，类似于氧化的HDL。 LDL（oxLDL）。此外，我们还将确定我们的修饰形式的HDL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CD 36是否也可以作为功能失调的HDL发挥作用。 巨噬细胞的受体。首先，我们将测试的假设，胆固醇酯（CE）交付从氧化 巨噬细胞的HDL形式由CD 36介导。第二，我们将确定是否acro-和/或HNE- 修饰的HDL可以诱导CD 36介导的信号级联。在目标3中，我们假设SR-BI缺乏， 由于缺乏HDL受体，高HDL-C和HDL-C清除受损的模型， 体内功能失调的HDL颗粒。为了验证这一新的假设，我们将首先确定HDL是否 从SR-BI-无效小鼠分离的含有氧化修饰。接下来，我们将测试HDL是否来自SR-BI-null 小鼠促进胆固醇在巨噬细胞中的积累，并诱导促炎反应， 抑制巨噬细胞迁移。总之，这些研究将揭示氧化修饰HDL 可以促进动脉粥样硬化的形成。我们预计，我们的研究结果将提供 新的见解对理解HDL功能的复杂性，并可能导致识别 治疗动脉粥样硬化的潜在靶点。