Atherosclerosis and its complications are leading causes of morbidity and mortality in this country. Thisdisease is now understood to be a chronic inflammatory condition with acute exacerbations thought to resultfrom plaque instability and the associated sudden exposure of flowing blood to the subendothelial lomponents of the lesions. This necrotic core of atherosclerotic lesions is composed of oxidized lipoproteinparticles and material from dead cells that contain inflammatory agonists and toxic lipids. Oxidation of lipoprotein particles fragments their phospholipids; some of these products chemicallyderivitized apolipoproteins to form the neo-epitopes recognized by scavenger receptors, others are cytotoxic,and still others are PAF analogs that initiate inflammatory signaling from this receptor for short chainphospholipids. PAF initiates clotting and white blood cell migration and activation, and oxidizedphospholipids that activate this receptor of innate immune cells are pro-thrombotic. These toxic and pro-inflammatory lipid agonists generated by phospholipid oxidation are hydrolyzed andinactivated by a lipoprotein-associated enzyme, PAF acetylhydrolase. However, hydrolysis in blood issignificantly slower than clearance in vivo, and individuals who completely lack this enzyme have only asmall increased risk of the complications of atherosclerosis. We propose that clearance in vivo mainly resultsfrom active uptake into endothelium with subsequent metabolism in a sequestered environment. We findapoE'7' hyperlipidemic mice have circulating inflammatory agonists of the receptor for Platelet-ActivatingFactor. We propose these accumulate because their clearance is slowed by competition for uptake by themore abundant phospholipid oxidation products that lack such inflammatory activity. Oxidized lipoproteins are toxic for unknown reasons. We find oxidized phospholipids alter mitochondrialfunction leading to the events associated with apoptosis, and propose oxidized phospholipids internalized byphysiologic transport systems initiate cell death in this manner. We will define elements of this previouslyoverlooked pathway to clear toxic phospholipids from the circulation in four aims: 1) Define the fate ofextracellular oxidized phospholipids 2) Define oxidized phospholipid uptake and metabolism by endothelialcells 3) Molecularly define oxidized phospholipid transporters in a model system 4) Determine whether thesystem that transports short chain phospholipids in yeast has functional mammalian homologs.
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