Proteoglycans (PG) play an important role in maintaining structural integrity, and the normal function and metabolism of the arterial wall. An accelerated synthesis of the connective tissue matrix, of which PG are important components, is a hallmark of atherosclerosis. A striking feature of PG is their heterogeneity with respect to size, charge density, characteristics of glycosaminoglycans (GAG) and core protein. A partially characterized chondroitin sulfate (CS)-PG from the arterial wall forms aggregates in the presence of hyaluronic acid and a link protein, and strongly binds atherogenic serum low density lipoproteins (LDL). The proposed research is based on the hypothesis that variation in intrinsic properties of PG influence both intracellular and extracellular lipid accumulation in the arterial wall. To test this hypothesis, research will focus on 1) characteristics of CS-PG subspecies or variants with respect to LDL binding, and 2) influence of LDL binding to CS-PG on intracellular and extracellular lipid accumulation. CS-PG fractions are isolated from the arterial tissue by dissociative solvent extraction and ultracentrifugation, followed by fractionation by gel filtration and by ion-exchange and hydrophobic interaction chromatographic procedures. CS-PG fractions from bovine aorta will be used to establish the characteristics of PG variants with respect to high- and low-affinity binding to LDL, and to study their influence on LDL conformation and LDL-mediated cholesteryl ester accumulation in macrophages, a process crucial to foam cell formation in atherosclerosis. PG variants are characterized with respect to the nature and molecular size of the core protein, number and nature of oligosaccharide and GAG chains on the core protein, and micro-heterogeneity of GAG in terms of molecular size, total sulfate, and proportion of glucuronic acid to iduronic acid. Alterations in LDL conformation associated with either volume or microscopic viscosity of the hydrocarbon region will be studied by measuring the fluorescence of pyrene-labeled LDL-PG complexes. Experimental models (rabbits) of arterial injury and atherosclerosis will be used to determine the effects of injury and repair and atherosclerosis on the PG variants. Measurements of in vivo aortic uptake of native and modified LDL in normal and LDL-receptor deficient mutant rabbits are planned to determine the contribution of PG to retention of LDL in normal and atherosclerotic tissues. These studies will help to clarify the role of PG in the pathogenesis of atherosclerosis.
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