RETENTION OF LIPOPROTEIN BY LESION-PRONE AORTA

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Diseases related to atherosclerosis are major causes of death in the United States. The risk of suffering from such diseases is increased when blood levels of low density lipoprotein (LDL) are elevated. However, all known risk factors for atherosclerosis can explain only about half of the risk, suggesting the importance of local factors acting at the level of the artery. The proposed studies examine the hypothesis that an early event in atherogenesis in rabbits is prolonged retention of large amounts of undegraded lipoprotein in artery in a form that does not readily exchange with the plasma. Prolonged retention of large amounts of LDL, and beta- VLDL, a prominent lipoprotein in plasma of cholesterol-fed rabbits, in artery could potentially allow conversion of these lipoproteins to form(s) which could recruit monocytes into artery and facilitate transformation of tissue macrophages into foam cells. These studies take advantage of the fact that cholesterol-fed rabbits develop early atherosclerosis in predictable aortic sites whereas adjacent aortic sites are resistant to atherosclerosis. Comparison of accumulation and retention of LDL within lesion-prone and adjacent lesion-resistant aorta at different times of cholesterol feeding should provide a sensitive means of determining whether accumulation and retention of LDL plays a role in atherogenesis. To further investigate this hypothesis, accumulation and retention of undegraded LDL within lesion-prone and lesion-resistant aorta will be examined when atherosclerosis is exacerbated by aortic injury produced by balloon catheter, for which there is a theoretical basis to suggest that sequestration of LDL within artery might be increased. Data for aortic accumulation of undegraded LDL and products of aortic degradation of LDL will be collected for different times after injection of radiolabeled LDL. By applying sophisticated mathematical computer modeling to those data, it will be possible to determine concentrations and retention times of LDL within aorta. It will also be possible to determine the relative roles that rates of entry, efflux, and degradation, and sequestration of LDL within aorta, play in determining accumulation and retention of undegraded LDL within aorta. For comparison, retention times of LDL within aorta will be determined from the above tracer data by an independent method. Sequestration of LDL will also be addressed by biochemical methods. The interaction of beta-VLDL with artery will be studied in a similar manner. These studies should provide insight into processes by which atherosclerosis develops in rabbits, and suggest possible ways that atherosclerosis in humans might be inhibited or prevented.