Molecular Basis of Oxidative Modification of LDL

LDL 氧化修饰的分子基础

• 批准号: 7589773
• 负责人: Robert Gerd Salomon
• 金额: $ 42.64万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589773
• 关键词: 4 hydroxynonenal; 4-oxo-2-nonenal; Acids; Aldehydes; Amino Acids; Apolipoproteins B; Area; Arterial Fatty Streak; Arterial Intimas; Arteries; Atherosclerosis; Binding; Biochemistry; Biological; Biology; Blood; CD36 gene; Cardiovascular Diseases; Cathepsins B; Cell Line; Cell physiology; Cells; Cellular biology; Chemicals; Chemistry; Cholesterol; Clinic; Complex; Consult; Development; Digestion; Elements; Endocytosis; Etiology; Event; Foam Cells; Foxes; Funding; Gel; Goals; Grant; Human; Image; Immunochemistry; Immunoprecipitation; Individual; Injury; Institution; Investigation; Joints; Knockout Mice; Knowledge; Lead; Lecithin; Ligands; Link; Lipid Chemistry; Lipid Peroxidation; Lipids; Lipoproteins; Liposomes; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Mass Spectrum Analysis; Mediating; Methodology; Modification; Molecular; Molecular Biology; Myocardial Infarction; N-methylacetamide-oxotremorine M; Nature; Pathogenesis; Pathologic; Phospholipids; Physiological; Pilot Projects; Post-Translational Protein Processing; Process; Protein Chemistry; Protein Fingerprints; Proteins; Proteomics; Public Health; Publications; Radiolabeled; Reagent; Research; Research Personnel; Risk Factors; Role; Sampling; Scientist; Specialist; Staging; Stroke; Two-Dimensional Gel Electrophoresis; Work; adduct; apolipoprotein B-100; atherogenesis; base; cellular targeting; crosslink; inhibitor/antagonist; insight; macrophage; macrophage scavenger receptors; mouse model; novel; oxidation; oxidative damage; oxidized lipid; oxidized low density lipoprotein; premature; programs; protein function; radiotracer; receptor; research study; success; tool; uptake

Substantial evidence suggests that the accumulation and subsequent poor processing of oxidatively modi- fied low density lipoprotein (oxLDL) by macrophages in the arterial wall contributes to the initial stages of atherogenesis. Oxidative modification of LDL involves the derivatization of its constituent apolipoprotein B by reactive aldehydic breakdown products of lipid peroxidation, including HNE. The chemistry of protein adduction by these aldehydes is highly complex and includes cross-linking. A major breakthrough of the current funding period was the finding that uptake of oxLDL by macrophages may be largely mediated by the recognition of oxidized phospholipids in oxLDL by CD36. We further discovered that the HNE-like products (and their derivatives) resulting from "mirror-image" oxidation of the arachidonyl and linoleyl chains of phospholipids serve as CD36 ligands. Further studies are proposed to bring thorough definition to the structural basis of oxLDL recognition by and accumulation within macrophage cells. Recent pilot studies suggest that oxidized constituents in oxLDL may interfere not only with lipoprotein processing within, but also cholesterol efflux from macrophage cells exposed to oxLDL. A major new aim of the next funding period is to clarify the nature of the inhibitory effects of oxLDL on cholesterol efflux. Our working hypothesis is that oxidative changes to LDL contribute to its uptake into and deficient processing within macrophage cells, and that oxLDL itself or constituents emanating from it inhibit one or more mechanisms of cholesterol efflux, all of which together act as an important determinant of foam cell formation. We will continue to define lipoxidation-dependent protein adduction chemistry, including mass spectrometric approaches to identifying macrophage proteins that are particularly susceptible to modification as a result of exposure of these cells to oxLDL. This latter aim will be aided by continued development of immunochemical probes for specific adducts, also useful for identifying the nature of late-stage adducts present in human atheroma. The new work proposed continues to take advantage of the pooled expertise of three individual investigators at neighboring research institutions, particularly with respect to the application of novel structurally-specific reagents and tools to cell biological studies. RELEVANCE TO PUBLIC HEALTH In the initial stages of atherosclerosis, the main cholesterol-carrying lipoprotein in blood, LDL, becomes oxidatively damaged (oxLDL), resulting in an attempt by cells lining the artery wall to scavenge the oxLDL and break it down. Our research is aimed at understanding why there is an accumulation of cholesterol in these cells because of their inability to efficiently break down the oxLDL and clear the released cholesterol.

大量证据表明，氧化修饰的积累和随后的不良加工 动脉壁中的巨噬细胞释放低密度脂蛋白（oxLDL）有助于早期阶段 动脉粥样硬化。 LDL 的氧化修饰涉及其成分载脂蛋白 B 的衍生化 脂质过氧化的反应性醛分解产物，包括 HNE。蛋白质的化学 这些醛的加合反应非常复杂并且包括交联。的重大突破 当前的资助期间发现巨噬细胞对 oxLDL 的摄取可能很大程度上是由 CD36 识别 oxLDL 中的氧化磷脂。我们进一步发现HNE类产品 （及其衍生物）由花生四烯基和亚油基链的“镜像”氧化产生 磷脂充当 CD36 配体。建议进一步研究，以彻底定义 oxLDL 被巨噬细胞识别并在巨噬细胞内积累的结构基础。最近的试点研究 表明 oxLDL 中的氧化成分不仅可能干扰其中的脂蛋白加工，而且还可能干扰 暴露于 oxLDL 的巨噬细胞的胆固醇流出。下一个资助期的一个主要新目标是 阐明 oxLDL 对胆固醇流出的抑制作用的性质。 我们的工作假设是，LDL 的氧化变化导致其被吸收和缺乏。 巨噬细胞内的加工，并且 oxLDL 本身或源自它的成分抑制一种或多种 更多胆固醇流出机制，所有这些机制共同充当泡沫细胞的重要决定因素 形成。我们将继续定义脂氧化依赖性蛋白质加合化学，包括质量 鉴定特别容易被修饰的巨噬细胞蛋白的光谱方法 由于这些细胞暴露于 oxLDL。后一个目标将得到持续发展的帮助 针对特定加合物的免疫化学探针，也可用于鉴定后期加合物的性质 存在于人类动脉粥样硬化中。拟议的新工作继续利用汇集的专业知识 邻近研究机构的三名独立调查员，特别是在申请方面 用于细胞生物学研究的新型结构特异性试剂和工具。 与公众健康的相关性 在动脉粥样硬化的初始阶段，血液中主要携带胆固醇的脂蛋白 LDL 变成 氧化损伤 (oxLDL)，导致动脉壁细胞尝试清除 oxLDL 并将其分解。我们的研究旨在了解为什么胆固醇会积累 这些细胞因为它们无法有效分解 oxLDL 并清除释放的胆固醇。