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SMOOTH MUSCLE CELL PROLIFERATION AND ATHEROSCLEROSIS

平滑肌细胞增殖和动脉粥样硬化

基本信息

批准号：
2459966
负责人：
WILLIAM D WAGNER
金额：
$ 17.83万
依托单位：
WAKE FOREST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-08-16 至 1999-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2459966
关键词：
aorta atherosclerosis atherosclerotic plaque cell differentiation cell type chromatography disease /disorder proneness /risk genetic disorder genetic strain glycoprotein structure heparan sulfate membrane activity pigeons proteoglycan tissue /cell culture vascular smooth muscle western blottings

项目摘要

Atherosclerosis is a complex pathological process that results from an interplay of genetic and environmental components. Many human beings develop accelerated atherosclerosis in the absence of known risk factors, and 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 studies 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 (HSPG). The studies are possible because of the availability of genetically selected atherosclerosis-susceptible White Carneau (WC) and -resistant Show Racer (SR) pigeons. Cultured aortic smooth muscle cells of the WC pigeons demonstrate a greater proliferation capacity than those of SR. Studies of cell surface HSPG have demonstrated reduced HSPG in WC compared to SR cells. The HSPG remaining on the surface of WC have low sulfated octasaccharide and possess a low content of a unique disaccharide containing iduronic acid 2-O-SO3. When WC HSPG are isolated and added to WC or SR smooth muscle cells in culture, a low antiproliferative effect is observed. SR HSPG block the proliferation of SR cells and are less effective in WC cells. The studies proposed are designed to determine the mechanisms that result in reduced HSPG on WC cells. Based on preliminary work, WC cells produce a pool of cell surface HSPG which is transported to the cell surface but rapidly lost. Possible roles of heparanases and proteinases in this loss will be explored in cell culture studies to define a mechanism that may be unique to the WC cells. Through pulse chase and kinetic modeling, the metabolism and cellular pathways involved in the fast-turning-over pool of HSPG will be examined. Studies of oligosaccharides of cell surface HSPG indicated that the reduced antiproliferative effect of HSPG resulted from the alterations in oligosaccharide sequences and secondary modifications (e.g., sulfation and position). Proposed studies will examine the activity of N-deacetylase/N sulfotransferase, the pivotal enzyme in the production of sulfated oligosaccharide blocks in HS to determine if structural variations in the saccharides of WC HS are attributed to differential enzyme activity. The ultimate goal of the proposal is to determine the role of HSPG in relation to smooth muscle cell proliferation in atherosclerosis and conditions such as restenosis following clinical angioplasty.

动脉粥样硬化是一种复杂的病理过程，遗传和环境因素的相互作用。许多人类在没有已知危险因素的情况下发生加速的动脉粥样硬化，有人提出有些人可能在基因上易患动脉粥样硬化的机制在动脉壁的水平。平滑肌细胞增殖动脉内膜在血管的发育和生长中具有关键的重要性，动脉粥样硬化病变在拟议的研究中，假设测试的是动脉粥样硬化的遗传易感性壁水平包括平滑肌的不同增殖反应细胞通过调节分子硫酸乙酰肝素蛋白聚糖（HSPG）。这些研究之所以可行，是因为遗传选择的动脉粥样硬化易感的白色猪（WC）和 - 抗性的Show Racer（SR）鸽子。培养的主动脉平滑肌细胞的WC鸽表现出更大的增殖能力比那些对细胞表面HSPG的研究表明，WC中HSPG减少与SR细胞相比。残留在WC表面的HSPG含量低，硫酸化八糖并具有低含量的独特二糖含有艾杜糖醛酸2-O-SO 3。当WC HSPG被分离并添加到在培养的WC或SR平滑肌细胞中，观察 SR HSPG抑制SR细胞增殖，在WC细胞中有效。拟议的研究旨在确定导致WC细胞上HSPG减少的机制。根据初步工作时，WC细胞产生细胞表面HSPG库，其被转运到细胞表面，但很快失去。乙酰肝素酶的可能作用在这种损失中的蛋白酶将在细胞培养研究中探索，定义了WC细胞特有的机制。通过脉冲追踪和动力学建模，代谢和细胞途径参与的对HSPG的快速周转池进行了考察。研究细胞表面HSPG寡糖的减少表明， HSPG的抗增殖作用可能与HSPG对细胞增殖的抑制作用有关。寡糖序列和二级修饰（例如，硫酸化和位置）。拟议的研究将检查N-脱乙酰酶/N 磺基转移酶，在硫酸生产的关键酶以确定HS中的寡糖块中的结构变化， WC-HS的差异归因于酶活性的差异。的该提案的最终目标是确定HSPG在以下方面的作用：动脉粥样硬化和其他疾病中的平滑肌细胞增殖临床血管成形术后再狭窄。