It has been proposed that modification of low density lipoprotein {LDL} by products of lipid peroxidation is a prerequisite to the pathogenesis of atherosclerosis. Recently attention has focused upon the possible relationship of the physical and chemical heterogeneity of circulating LDL to predisposition to atherosclerosis. Lipoprotein heterogeneity is marked by a decline in the ratio of lipid to protein and concomitant decline in particle diameter. Smaller, more dense particles as compared to larger, buoyant LDL display enhanced susceptibility to transition metal-induced oxidation thought to mimic arterial wall modification in vivo. The mechanisms accounting for the susceptibility of LDL subpopulations to oxidation have yet to be elucidated. Our preliminary investigations, based upon fractionation of human LDL by ion-exchange on fast protein liquid chromatography, provide a novel, potential mechanism. It is the premise of this application that lipoprotein-bound sialic acid, owing to ability to complex transition metals and transition metal- containing molecules, enhances the susceptibility of LDL and other apoB- containing lipoproteins to oxidation processes. The first specific aim will establish the role of sialic acid in mediating biochemical changes characteristic of transition metal-induced oxidation of human LDL. The ability of sialic acid-rich LDL to associate with lipid transfer protein and plasma neuraminidase will be tested. The second specific aim will examine the interaction of sialic acid LDL with arterial wall components and examine the ability of cocultures of human endothelial and smooth muscle cells to mediate conversion of sialyl-rich LDL to biologically active, minimally modified LDL. The proposed studies aim to establish a mechanistic link between the chemical and structural heterogeneity of circulating LDL and the subsequent events of modification of arterial wall-entrapped LDL thought to play initiating and sustaining roles in atherosclerosis.
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