Plasmalogen-derived bioactive lipids in atherosclerosis

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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.