SMOOTH MUSCLE CELL PROLIFERATION AND ATHEROSCLEROSIS

动脉粥样硬化是一个复杂的病理过程，由 遗传因素和环境因素的相互作用。尽管有几个风险 疾病发生的因素(例如，血浆胆固醇、血压) 已经被描述过，许多人患上加速的动脉粥样硬化 在没有已知风险因素的情况下。有人提出，有些人 个体可能在遗传上易患动脉粥样硬化 这是在动脉壁水平上运行的机制的结果。 动脉内膜中平滑肌细胞的增殖是关键 在动脉粥样硬化病变的发展和生长中的重要性。在……里面 拟议的研究要检验的假设是，基因 动脉壁水平对动脉粥样硬化的易感性包括 血管平滑肌细胞增殖反应的差异性表现 通过调节分子硫酸乙酰肝素蛋白多糖(HS-PG)。这个 研究之所以可能，是因为有了经过基因选择的 易患动脉粥样硬化的白肉(WC)和抗动脉粥样硬化的赛车手 (高级)鸽子。通过一种未知的机制(S)，血管平滑肌细胞 易患动脉粥样硬化的WC鸽子表现出更大的 培养中的增殖能力。细胞表面的初步检查 与SR相比，WC中的蛋白多糖显示HS-PG减少 细胞，以及从两个细胞中分离的HS-PG的结构变异 类型。通过这项提案中概述的一系列研究， 细胞表面HS-PG的结构、数量和代谢特性 大鼠腹主动脉平滑肌细胞培养的特性及比较 和SR鸽子。放射性前驱体及其新技术 将使用低聚糖图谱来确定结构 多样性导致HS-PG分子功能性质的改变 在这些牢房里。将研究HS链的详细结构。 将使用脉冲追逐和动力学建模技术来描述 细胞表面HS-PG的代谢和细胞通路特征 并明确HS-PG在调节WC和SR顺畅中的作用 肌肉细胞的增殖状态和潜能。的最终目标是 建议确定HS-PG在细胞中的作用 以动脉粥样硬化易感鸽子的增殖为模型 人类动脉粥样硬化。

Atherosclerosis is a complex pathological process that results from an interplay of genetic and environmental components. Although several risk factors for disease development (e.g., plasma cholesterol, blood pressure) have been described, many human beings develop accelerated atherosclerosis in the absence of known risk factors. It has been proposed that some individuals may be genetically predisposed to develop atherosclerosis as a result of mechanisms operating at the level of the arterial wall. Proliferation of smooth muscle cells in the arterial intima is of key importance in the development and growth of atherosclerotic lesions. In the proposed study the hypothesis to be tested is that genetic susceptibility to atherosclerosis at the artery wall level includes a differential proliferative response of smooth muscle cells manifested through a regulatory molecule heparan sulfate proteoglycan (HS-PG). The studies are possible because of the availability of a genetically selected atherosclerosis-susceptible White Carneau (WC) and -resistant Show Racer (SR) pigeon. Through an unknown mechanism(s) the smooth muscle cells of the atherosclerosis-susceptible WC pigeon demonstrate a greater proliferation capacity in culture. Preliminary examination of cell surface proteoglycans has demonstrated a reduction in HS-PG in WC compared to SR cells, and structural variations in the HS-PG isolated from the two cell types. Through a series of studies outlined in this proposal, the structure, amount and metabolic properties of the cell surface HS-PG will be characterized and compared in cultured aortic smooth muscle cells of WC and SR pigeons. Radioactive precursors and the new technique of oligosaccharide mapping will be used to determine whether structural diversities result in altered functional properties of the HS-PG molecule in these cells. The detailed structure of the HS chain will be examined. Pulse chase and kinetic modeling techniques will be sued to describe the metabolic and cellular pathways characteristic for the cell surface HS-PG and to define the role of HS-PG in regulation of the WC and SR smooth muscle cell proliferative state and potential. The ultimate goal of the proposal is to determine the role of HS-PG in relation to cell proliferation in the atherosclerosis-susceptible pigeon as a model for human atherosclerosis.