The known atherosclerosis """"""""risk factors"""""""" such as hyperlipoproteinemia and hypertension do not fully explain the atherosclerotic process, suggesting that the artery wall itself exerts a major influence. A vital unanswered question concerns the mechanism of lipid accumulation in the artery wall. One current hypothesis involves the interaction of arterial wall intercellular polyanionic complex carbohydrates, the proteoglycans (PG) and plasma lipoprotein as the plasma lipoproteins traverse the arterial wall. This proposal involves studies of arterial wall PG, specifically chondroitin sulfate (CS) and dermatan sulfate (DS) PG monomers to test the hypothesis that compositional and/or conformational changes and thus function are important factors in the initiation and/or perhaps more importantly, in influencing the rate of atherosclerosis development. The studies involve dissociative extraction, purification of CS-PG and DS-PG and characterization of monomer structure. The model systems used will be the normal human aorta, areas of fatty streak and atherosclerotic plaque, and the arteries from genetically selected atherosclerosis-susceptible White Carneau and -resistant Show Racer pigeons. Studies are designed to provide detailed information on the structure, especially the oligosaccharides of the CS-PG. For DS-PG, monomer size, number of glycosaminoglycan chains, carbohydrate composition of glycosaminoglycan chains, and the nature and composition of the oligosaccharide component will be examined in an attempt to relate the structural features to a potential for greater plasma low density lipoprotein binding. Through electron microscopic studies of isolated DS-PG and CS-PG monomers and CS-PG-hyaluronic acid complexes we will assess structural characteristics, relate these observations to the biochemically defined structure and determine the significant changes in monomers in both the White Carneau pigeon artery and in the human atherosclerotic plaque. Several in situ localization studies of PG monomers using polyclonal and specific monoclonal antibodies will be used to localize CS-PG and DS-PG in the artery wall and to investigate changes during atherosclerosis progression. The significance of the project lies in a better understanding of the structure and function of PG in normal artery and a further definition of how these matrix components may influence the development of atherosclerosis. Ultimately the research could provide a further understanding of the initiation and progression of the atherosclerotic plaque.
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