Plasmalogen-derived bioactive lipids in atherosclerosis

描述（由申请人提供）：髓过氧化物酶（MPO）和MPO衍生产品已在人类动脉粥样硬化病变中被检测到。我们最近证明了mpo衍生的活性氯化物质（RCS）靶向组织质原的乙烯醚键，导致α -氯脂肪醛（α - ci - fald）和溶血磷脂酰胆碱（UnsatLPC）的不饱和分子物质的产生。此外，初步研究表明α - ci - fald和UnsatLPC存在于人类动脉粥样硬化病变中。除了α - ci - fald和UnsatLPC外，初步研究表明，mpo衍生的RCS对等离子醛原乙烯醚键的攻击可以产生：1)完整的等离子醛原在乙烯醚键上被氯化；2)烷基醚磷脂（即血小板活化因子PAF的前体）；3)含氯醇的溶血磷脂酰胆碱分子种；4)含有α - ci - fld - n修饰乙醇胺极性头基的磷脂酰乙醇胺分子种；5) α - ci - fld - n修饰肽。初步数据表明，这些rcs衍生的plasmalogen氧化产物具有化学引诱剂、改变基因转录、诱导COX-2和iNOS的表达以及内皮细胞表面p -选择素的表达等潜在的生物学作用。这些初步发现导致了这样的假设，即RCS对组织和脂蛋白磷脂原的靶向是一种生化机制，负责产生一种新的动脉粥样硬化脂质介质家族。这一假设将通过以下具体目标进行验证：Aim 1的目标是在人类动脉粥样硬化病变和被激活的单核细胞和巨噬细胞靶向的组织中识别rcs衍生的plasmalogen氧化产物。Aim 2的目的是证明由RCS攻击的plasmalogen是一种重要的生化机制，可以产生促动脉粥样硬化的脂质介质。目的3是确定rcs衍生的plasmalogen氧化产物在细胞增殖和死亡中的作用。

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.