Plasmalogen-derived bioactive lipids in atherosclerosis

描述（由申请方提供）：在人类动脉粥样硬化病变中检测到髓过氧化物酶（MPO）和MPO衍生产物。我们最近已经证明，MPO衍生的反应性氯化物质（RCS）靶向组织缩醛磷脂的乙烯基醚键，导致产生α-氯-脂肪醛（α-CI-β-D）和溶血磷脂酰胆碱（UnsatLPC）的不饱和分子物质。此外，初步研究表明，人动脉粥样硬化病变中存在α-CI-β D和UnsatLPC。除了α-C1-C1 D和UnsatLPC之外，初步研究已经证明，通过MPO衍生的RCS攻击缩醛磷脂乙烯基醚键可以产生：1）在乙烯基醚键上氯化的完整缩醛磷脂; 2）烷基醚磷脂（即，血小板活化因子，PAF的前体）; 3）含有氯代醇的溶血磷脂酰胆碱分子种类; 4）含有α-Cl-β-D-N-修饰的乙醇胺极性头部基团的磷脂酰乙醇胺分子种类;和5）α-Cl-β-D-N-修饰的肽。初步数据表明，这些RCS衍生的缩醛磷脂氧化产物的潜在生物学作用表明，它们是化学引诱物，改变基因转录，并引起考克斯-2和iNOS表达以及内皮细胞表面P-选择素表达。这些初步的发现导致了这样的假设，即RCS对组织和脂蛋白缩醛磷脂的靶向作用是一种生化机制，该机制负责产生一种新的动脉粥样硬化介体家族。该假设将通过以下特定目的进行检验：目的1的目的是鉴定人动脉粥样硬化病变和活化单核细胞和巨噬细胞靶向组织中的RCS源性缩醛磷脂氧化产物。目的2的目的是证明RCS攻击缩醛磷脂是一种重要的生化机制，可产生促动脉粥样硬化的促动脉粥样硬化介质。目的3是确定RCS衍生的缩醛磷脂氧化产物对细胞增殖和死亡的作用。

DESCRIPTION (provided by applicant): Myeloperoxidase (MPO) and MPO-derived products have been detected in human atherosclerotic lesions. We have recently demonstrated that MPO-derived, reactive chlorinating species (RCS) target the vinyl ether bond of tissue plasmalogens resulting in the production of alpha-chloro-fatty aldehyde (alpha-CI-FALD), and unsaturated molecular species of lysophosphatidylcholine (UnsatLPC). Furthermore, preliminary studies show that alpha-CI-FALD and UnsatLPC are present in human atherosclerotic lesions. In addition to alpha-CI-FALD and UnsatLPC, preliminary studies have demonstrated that attack of the plasmalogen vinyl ether bond by MPO-derived RCS can yield: 1) intact plasmalogens that are chlorinated across the vinyl ether bond; 2) alkyl ether phospholipids (i.e., precursors of platelet activating factor, PAF); 3) lysophosphatidylcholine molecular species containing chlorohydrins; 4) phosphatidylethanolamine molecular species containing alpha-CI-FALD-N-modified ethanolamine polar head groups; and 5) alpha-CI-FALD-N-modified peptides. The potential biological role of these RCS-derived plasmalogen oxidation products is suggested by preliminary data showing that they are chemoattractants, alter gene transcription and elicit both COX-2 and iNOS expression as well as endothelial cell surface expression of P-selectin. These preliminary findings have led to the hypothesis that the targeting of tissue and lipoprotein plasmalogens by RCS is a biochemical mechanism responsible for the generation of a novel family of lipidic mediators of atherosclerosis. This hypothesis will be tested by the following specific aims: The goals of Aim 1 are to identify the RCS-derived plasmalogen oxidation products in human atherosclerotic lesions and in tissues targeted by activated monocytes and macrophages. The goals of Aim 2 are to demonstrate that plasmalogen attack by RCS is an important biochemical mechanism that produces lipidic mediators that are proatherogenic. The goals of Aim 3 are to determine the role of RCS-derived plasmalogen oxidation products on cell proliferation and death.