AORTIC PROTEOGLYCANS AND ATHEROSCLEROSIS

蛋白多糖(PG)通过以下途径参与动脉粥样硬化过程 它们结合和保留血浆低密度脂蛋白的能力 在动脉壁内。随着动脉粥样硬化的进展，动脉PG， 尤其是硫酸皮肤素(DSPG)增加。我们的初步数据 表明两个不同的DSPG分子(Biglycan和Decorin)是 存在于人的大动脉中。随着动脉粥样硬化而增加的DSPG型 而增加的后果目前尚不清楚。的目标是 本提案旨在定义DSPG的结构、代谢和功能 在发展中的人类动脉粥样硬化斑块中。假设是这样的 动脉粥样硬化的进展与血管顺应性改变有关 肌肉细胞代谢导致DSPG产生的调节 打字。这种调节机制在决定动脉粥样硬化的速度中起着关键作用 进步了。动脉平滑肌细胞DSPG的产生可以 受环境因素的影响(例如，生长因素、 巨噬细胞、胆固醇积累)以及内在遗传 细胞的潜力。使用综合方法采用 生化、组织学、免疫组织化学和电子显微镜 人主动脉二聚糖和粘附素的技术、性质 与动脉壁的动脉粥样硬化改变或老化有关。 结构研究将包括核心蛋白和 糖胺聚糖(GAG)。GAG大小、链亚结构和含量 艾杜糖醛酸将被检测，因为这些性质影响潜在的 与低密度脂蛋白结合。器官培养中的代谢研究将确定 DSPG的增加是合成增加或周转减少的结果。一个 模拟动脉粥样硬化内细胞间相互作用的模型系统 斑块将用于研究培养的人中DSPG的调节 动脉平滑肌细胞暴露于巨噬细胞条件培养液中。 几项研究的预期结果包括刺激二聚糖， 增强Biglycan与血浆低密度脂蛋白的结合能力和亲和力，以及 随后培养的巨噬细胞摄取LDLPG，从而解释了一种新的 巨噬细胞脂质负荷与血管生成的机制 动脉粥样硬化就会发生。最终的影响包括选择性的 旨在延缓动脉粥样硬化的发展。

Proteoglycans (PG) are implicated in the atherosclerotic process through their capacity to bind and retain plasma low density lipoproteins (LDL) within the artery wall. As atherosclerosis progresses, arterial PG, particularly dermatan sulfate (DSPG) increase. Our preliminary data indicate that two distinct DSPG molecules (biglycan and decorin) are present in human aorta. The DSPG type which increases with atherosclerosis and the consequences of the increase are presently unknown. The goal of this proposal is to define the structure, metabolism and function of DSPG in the developing human atherosclerotic plaque. The hypothesis is that progression of atherosclerosis is associated with an alteration of smooth muscle cell metabolism resulting in a modulation in production of DSPG type. The modulation is critical in determining how fast atherosclerosis progresses. Production of arterial smooth muscle cell DSPG can be influenced by environmental factors (e.g. growth factors, presence of macrophages, cholesterol accumulations) as well as the intrinsic genetic potential of the cells. Using a comprehensive approach employing biochemical, histological, immunohistochemical, and electron microscopic techniques, properties of human aortic biglycan and decorin will be related to atherosclerotic changes or aging of the artery wall. Structural studies will include properties of core proteins and glycosaminoglycans (GAG). GAG size, chain substructure and content of iduronic acid will be examined since these properties influence potential binding to LDL. Metabolic studies in organ cultures will determine if increased DSPG results from increased synthesis or decreased turnover. A model system that mimics cell-cell interactions within the atherosclerotic plaque will be used to investigate modulations of DSPG in cultured human arterial smooth muscle cells exposed to macrophage conditioned media. Anticipated results of several studies include a stimulation of biglycan, increased binding capacity and affinity of biglycan to plasma LDL, and subsequent uptake of LDLPG by cultured macrophages, thus explaining a new mechanism whereby lipid loading of macrophages and development of atherosclerosis occurs. The ultimate implications include selective targeting to retard atherosclerosis development.