Molecular Basis of Oxidative Modification of LDL

LDL 氧化修饰的分子基础

• 批准号: 7218123
• 负责人: LAWRENCE M SAYRE
• 金额: $ 40.26万
• 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/7218123
• 关键词: Molecular; Basis; Oxidative; Modification; LDL

DESCRIPTION (provided by applicant): Substantial evidence suggests that the accumulation and subsequent poor processing of oxidatively modified 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.

描述（由申请人提供）：大量证据表明，动脉壁中巨噬细胞氧化修饰的低密度脂蛋白（oxLDL）的积累和随后的不良加工有助于动脉粥样硬化的初始阶段。LDL的氧化修饰涉及脂质过氧化反应醛分解产物（包括HNE）对其成分载脂蛋白B的衍生化。这些醛的蛋白质内聚的化学反应是非常复杂的，包括交联。当前资助期的一个重大突破是发现巨噬细胞对oxLDL的摄取可能主要是由CD36对oxLDL中氧化磷脂的识别介导的。我们进一步发现，由花生四烯酰基和亚油基磷脂链的“镜像”氧化产生的类hne产物（及其衍生物）可作为CD36配体。我们建议进一步研究巨噬细胞对oxLDL的识别和积累的结构基础。最近的初步研究表明，oxLDL中的氧化成分不仅可能干扰体内的脂蛋白加工，还可能干扰暴露于oxLDL的巨噬细胞的胆固醇外排。下一个资助期的一个主要新目标是阐明oxLDL对胆固醇外排的抑制作用的性质。