Reactive oxygen species are associated with altered vascular function in atherosclerosis. The nature and complexity of lesion development in atherosclerosis suggest that this process may have several etiologies. A critical component in the pathogenesis of this disease is the oxidative modification of low density lipoproteins. The studies proposed in this application are designed to provide new information concerning the role of modified low density lipoproteins in the generation of oxygen free radicals in vascular cells. We hypothesize that exposure of vascular endothelium and smooth muscle cells to oxidized low density lipoproteins contributes to vascular dysfunction in this disease via stimulation of cellular oxidant production. The primary goal of the proposed research is to describe the mechanisms by which vascular cells' production of reactive oxygen species is altered upon exposure to modified lipoprotein. In testing this hypothesis, we will address three primary points: 1. Define the influence of oxidatively modified low density lipoprotein on cellular production of reactive species. 2. Identify mechanisms accounting for enhanced cellular steady-state concentrations of reactive species. 3. Examine the effects of site-directed superoxide scavengers on cellular oxidant generation and superoxide-dependent vascular dysfunction. The results of the proposed research will broaden our current understanding of basic mechanisms of altered vascular function in atherosclerosis. The sponsor's laboratory, well established in the field of reactive oxygen biochemistry, provides a fertile atmosphere in which to answer these questions. The experience and training that the candidate will gain by performing these studies, and by studies in graduate level cell and molecular biology courses will form a solid framework for a successful independent investigative career.
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