Previous work from the investigator's laboratory and elsewhere has shown that LDL oxidative behavior varies among individuals and is associated with variations in the distribution of LDL particles among subspecies differing in size, density and chemical composition. The objectives of the proposed research are (1) to define physical and chemical determinants of LDL oxidative susceptibility, with emphasis on factors contributing to the enhanced oxidizability of smaller, more dense LDL particles, (2) to investigate whether differences in physical-chemical attributes and oxidative behavior lead to differences in atherogenic effects and (3) to evaluate whether differences in oxidative behavior arise from the properties of LDL precursors, i.e., IDL and VLDL. The first objective will be addressed by studying LDL oxidation in vitro, using both hydrophilic and lipophilic chemical oxidizing agents, as well as cellular oxidizing systems. The biological consequences of differences in oxidative behavior will be addressed by comparing oxidized buoyant and dense LDL for their ability to promote atherogenic processes in arterial cells, namely, stimulation of endothelial cell-monocyte interactions and promotion of LDL uptake and degradation by macrophages. Finally, metabolic influences on LDL behavior will be evaluated by investigating VLDL and IDL subfractions from pattern A and pattern B individuals and assessing whether properties of these precursor particles are associated with differences in the oxidative behavior of their LDL products. It is expected that these studies will lead to a more comprehensive understanding of the heterogeneity in atherosclerosis risk and will aid in the development of effective and individualized regimens for reducing risk.
