A good deal of evidence both in vitro and in vivo now supports the hypothesis that oxidative modification of LDL enhances its atherogenicity in several ways. Unlike native LDL, it is cytotoxic; it is a chemoattractant for circulating monocytes; and it is recognized by the scavenger receptors of the macrophage, thus contributing to formation of foam cells in the fatty streak. The studies proposed will attempt to elucidate the mechanisms by which LDL undergoes oxidative modification, how the modified form interacts with cells of the artery wall and how these changes contribute to the pathogenesis of atherosclerosis. The potential role of lipoxygenases in oxidative modification will be studied in cultured cells, utilizing gene transfection and """"""""gene knockout"""""""" experiments with antisense mRNA to critically evaluate the role of lipoxygenases. The potential role of superoxide anion will be evaluated in continuing studies of normal monocytes and monocytes from patients lacking the NADPH oxidase system. Finally, the role of peroxidases and peroxides will be evaluated. Properties of the LDL particle that influence its susceptibility to oxidation will be studied, including its fatty acid composition, its initial content of lipoperoxides and its phopholipase A2 activity. In parallel, properties f the cell that may affect its ability to oxidatively modify will be studied. Recent evidence has been presented that LDL enriched in oleic acid is strongly resistant to oxidative modification. These studies will be pursued in an attempt to pinpoint the molecular mechanism underlying the resistance. Compounds that inhibit the ability of the cell to oxidatively modify will be studied. Evidence that an additional receptor(s) for uptake of oxidized LDL (in addition to the acetyl LDL receptor) will be pursued and attempts will be made to identify the """"""""natural"""""""" ligand(s) for these scavenger receptors. Finally, the metabolic consequences to the macrophage of binding and uptake of oxidatively modified LDL will be studied.
