The defining characteristic of atherosclerosis is the accumulation of cholesterol within the artery wall. This process requires the retention of apoB100- or apoB48-lipoproteins in the subendothelial space. The PI and his colleagues present data that support a hypothesis that the one portion of lipoproteins that causes them to be retained in the subendothelial space is within the NH2- terminal region of apoB (NTAB). A series of experiments is proposed to test this hypothesis in vivo and then to more precisely define the portion of apoB that is required for production of an atherogenic particle.
Aim 1 is to determine the biochemical properties of the interaction between apoB100- and apoB48- lipoproteins and matrix proteins. Lipoprotein-matrix molecular interactions will be studied using isolated matrix components and perfused blood vessels. Our objective will be to define the region of apoB that allows lipoprotein-matrix association.
Aim 2 is to block atherosclerosis development in mice by inhibiting apoB binding to arteries. We have overexpressed apoB17 by adenoviral infection and by creating transgenic mice. We show that apoB17 does not alter plasma levels of lipoproteins and is not associated with the atherogenic lipoproteins. Atherosclerosis-prone mouse models will be used to test the hypothesis that by competing for lipoprotein binding to matrix, soluble apoB fragments decrease atherosclerosis.
Aim 3 is to create atherosclerosis in mice using NTAB associated with a lipid-binding region of apoB. We have produced a construct in which a beta-sheet lipid-binding region of apoB (from apoB29-36) is attached to apoB17. We predict that when this protein is expressed in the liver, it will produce small, cholesterol-containing lipoproteins that will cause atherosclerosis. In contrast, similar levels of cholesterol-containing lipoproteins produced with apoAI attached to this same lipid-binding region will not be atherogenic. These experiments will explain why apoB-containing lipoproteins are pathological. Moreover, the experiments are significant for our understanding of atherosclerosis development and may demonstrate molecular methods to alter apoB retention that could be used in treatment and preventative therapies.
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