RETENTION OF LIPOPROTEIN BY LESION-PRONE AORTA

与动脉粥样硬化有关的疾病是美国人死亡的主要原因。 States. 当血液中的蛋白质含量过高时， 低密度脂蛋白（LDL）水平升高。 然而，所有已知的 动脉粥样硬化的危险因素只能解释大约一半的风险， 这表明在国家一级发挥作用的当地因素的重要性， 动脉 拟议中的研究检验了这样一种假设，即 家兔动脉粥样硬化的形成是大量的 动脉中不易交换的未降解脂蛋白 等离子。 长期保留大量的低密度脂蛋白，和β- 极低密度脂蛋白，一种主要的脂蛋白在血浆中的胆固醇喂养的兔子， 动脉可能允许这些脂蛋白转化为 它可以将单核细胞募集到动脉中， 组织巨噬细胞变成泡沫细胞。 这些研究利用了 事实上，高胆固醇喂养的兔子会在 可预测的主动脉部位，而相邻的主动脉部位抵抗 动脉粥样硬化 LDL在体内蓄积和保留的比较 病变倾向和相邻病变抵抗主动脉在不同时间的 胆固醇喂养应该提供一种敏感的方法来确定是否 LDL的积累和保留在动脉粥样硬化形成中起作用。 到 进一步研究这一假设，积累和保留 易损伤和抗损伤主动脉内未降解的LDL将 当动脉粥样硬化因主动脉损伤而加剧时进行检查 球囊导管，有理论依据表明， LDL在动脉内的滞留可能增加。 主动脉数据 未降解LDL和LDL主动脉降解产物的蓄积 将在注射放射性标记的LDL后的不同时间采集。 通过对这些数据进行复杂的数学计算机建模， 将有可能确定LDL的浓度和保留时间 主动脉内。 还可以确定 低密度脂蛋白的进入、流出、降解和隔离率 在主动脉内，发挥决定积累和保留未降解的 主动脉内的LDL。 为了比较，LDL在主动脉内的保留时间将 通过独立的方法从上述示踪剂数据中确定。 LDL的螯合也将通过生物化学方法来解决。 的 将以类似方式研究β-VLDL与动脉的相互作用。 这些研究应该提供对过程的深入了解， 动脉粥样硬化的发展，并提出了可能的方式， 可以抑制或预防人类的动脉粥样硬化。

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.