AORTIC PROTEOGLYCANS AND ATHEROSCLEROSIS

已知的动脉粥样硬化“危险因素”，如高脂蛋白血症和 高血压并不能完全解释动脉粥样硬化的过程，提示 动脉壁本身会产生很大的影响。一个重要的未被回答的问题 这个问题涉及动脉壁中脂质堆积的机制。 目前的一种假说涉及动脉壁的相互作用 细胞间多阴离子复合体碳水化合物、蛋白多糖(PG)和 血浆脂蛋白作为血浆脂蛋白横穿动脉壁。 这项建议涉及对动脉壁PG的研究，特别是 硫酸软骨素(CS)和硫酸皮肤素(DS)PG单体测试 假设成分和/或构象发生变化，从而 功能是启动和/或可能更多的重要因素 重要的是，在影响动脉粥样硬化的发展速度方面。这个 CS-PG和DS-PG的分离提取、纯化研究 以及单体结构的表征。使用的模型系统将是 正常人的大动脉，脂肪条纹和动脉粥样硬化斑块， 来自基因选择的动脉粥样硬化易感性的动脉 白色卡诺和耐受的赛马鸽子。研究的目的是 提供有关结构的详细信息，特别是 CS-PG的低聚糖。对于DS-PG，单体尺寸、数量 糖胺多糖链、糖胺多糖的碳水化合物组成 链，以及寡糖成分的性质和组成 将被检查，以尝试将结构特征与 更大的血浆低密度脂蛋白结合的可能性。穿过 DS-PG和CS-PG单体分离的电子显微镜研究 我们将评估CS-PG-透明质酸络合物的结构特征， 将这些观察结果与生物化学定义的结构和 确定白葡萄酒和红葡萄酒中单体的显著变化 在鸽子动脉和人类动脉粥样硬化斑块中。几个现场 PG单体的多克隆和特异性定位研究 将用单抗定位CS-PG和DS-PG在 并研究动脉粥样硬化进展过程中的变化。 这个项目的意义在于更好地理解了 正常动脉中PG的结构和功能及对PG的进一步定义 这些矩阵组件可能如何影响 动脉硬化。最终，这项研究可以提供进一步的 对动脉粥样硬化发生发展的认识 斑块。

The known atherosclerosis "risk factors" such as hyperlipoproteinemia and hypertension do not fully explain the atherosclerotic process, suggesting that the artery wall itself exerts a major influence. A vital unanswered question concerns the mechanism of lipid accumulation in the artery wall. One current hypothesis involves the interaction of arterial wall intercellular polyanionic complex carbohydrates, the proteoglycans (PG) and plasma lipoprotein as the plasma lipoproteins traverse the arterial wall. This proposal involves studies of arterial wall PG, specifically chondroitin sulfate (CS) and dermatan sulfate (DS) PG monomers to test the hypothesis that compositional and/or conformational changes and thus function are important factors in the initiation and/or perhaps more importantly, in influencing the rate of atherosclerosis development. The studies involve dissociative extraction, purification of CS-PG and DS-PG and characterization of monomer structure. The model systems used will be the normal human aorta, areas of fatty streak and atherosclerotic plaque, and the arteries from genetically selected atherosclerosis-susceptible White Carneau and -resistant Show Racer pigeons. Studies are designed to provide detailed information on the structure, especially the oligosaccharides of the CS-PG. For DS-PG, monomer size, number of glycosaminoglycan chains, carbohydrate composition of glycosaminoglycan chains, and the nature and composition of the oligosaccharide component will be examined in an attempt to relate the structural features to a potential for greater plasma low density lipoprotein binding. Through electron microscopic studies of isolated DS-PG and CS-PG monomers and CS-PG-hyaluronic acid complexes we will assess structural characteristics, relate these observations to the biochemically defined structure and determine the significant changes in monomers in both the White Carneau pigeon artery and in the human atherosclerotic plaque. Several in situ localization studies of PG monomers using polyclonal and specific monoclonal antibodies will be used to localize CS-PG and DS-PG in the artery wall and to investigate changes during atherosclerosis progression. The significance of the project lies in a better understanding of the structure and function of PG in normal artery and a further definition of how these matrix components may influence the development of atherosclerosis. Ultimately the research could provide a further understanding of the initiation and progression of the atherosclerotic plaque.