CORONARY ARTERY RESTENOSIS--A MAJOR CARDIOLOGY PROBLEM

冠状动脉再狭窄——一个重大的心脏病学问题

• 批准号: 3369181
• 负责人: James T. Willerson
• 金额: $ 19.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-01 至 1997-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3369181
• 关键词: RNase protection assay; angiotensin II; atherosclerosis; coronary occlusion /thrombosis; disease /disorder model; dogs; fibroblast growth factor; intraluminal angioplasty; laboratory rat; molecular pathology; northern blottings; platelet aggregation; restenosis; serotonin; thromboxanes; vasoactive agent

Neointimal fibroproliferation is the pathological process that underlies restenosis after angioplasty. The pathophysiological events resulting in neointimal proliferation can be divided into three stages: the acute initiating phase in response to injury, the intermediate phase of smooth muscle migration and proliferation, and the chronic perpetuating phase of neointimal proliferation. The purpose of this research will be to elucidate basic mechanisms involved in the initiating phase of neointimal fibroproliferation following mechanically-induced endothelial injury resulting from coronary artery angioplasty in canine models with and without intrinsic coronary atherosclerosis. Based on mechanistic insights gained, we hope to develop protective therapies that prevent neointimal fibroproliferation following balloon angioplasty. Cell culture tissues and chronically instrumented canine models with and without native coronary artery atherosclerosis will be used to rest the following hypotheses: (a) Platelet aggregation, platelet-vessel wall interaction and the release f platelet-derived products are necessary for the development of neointimal fibroproliferation; (b) Platelet-derived vasoactive substances (thromboxane A2 and serotonin) and vessel wall- derived vasoactive substances (angiotensin II) interact synergistically with other locally generated growth factors to initiate the process of neointimal fibroproliferation and restenosis that occurs after coronary artery angioplasty; (c) Fibroblast growth factor and its receptors play a role in the neointimal proliferation that occurs following balloon angioplasty, and they are increased following endothelial injury from coronary artery angioplasty in dogs with and without coronary artery atherosclerosis; and (d) An inhibitor of smooth muscle cell proliferation, saporin, linked to fibroblast growth factor or to specific monoclonal antibodies directed at fibroblast growth factor receptors, in conjunction with inhibitors of platelet aggregation (e.g. antagonists of thromboxane A2 and serotonin) markedly attenuates neointimal proliferation following endothelial injury induced by angioplasty.

新生内膜纤维增殖是其基础的病理过程。 血管成形术后再狭窄。由此引发的病理生理事件 在新血管内膜的增殖可分为三个阶段：急性 启动阶段对损伤的反应，中间阶段的平稳 肌肉的迁移和增殖，以及慢性永久期 新生内膜增殖症。这项研究的目的将是 阐明新生血管内膜启动阶段的基本机制 机械性内皮损伤后的纤维增殖 冠脉成形术所致的犬冠脉病变 没有固有的冠状动脉粥样硬化。基于机械论 获得的见解，我们希望开发保护性疗法来预防 球囊血管成形术后新生内膜纤维增生。细胞 培养组织和慢性器械犬模型 没有天然冠状动脉粥样硬化就会被用来休息 以下假设：(A)血小板聚集、血小板-血管壁 相互作用和血小板衍生产物的释放是必要的 新生血管内膜纤维增殖的发展；(B)血小板来源 血管活性物质(血栓素A2和5-羟色胺)和血管壁- 衍生的血管活性物质(血管紧张素II)协同作用 与其他本地产生的增长因素一起启动这一进程 冠状动脉术后发生的新生内膜纤维增殖和再狭窄 动脉血管成形术；(C)成纤维细胞生长因子及其受体的作用 球囊扩张后血管内膜增生中的作用 血管成形术，它们在血管内皮损伤后增加 犬冠状动脉成形术的实验研究 动脉粥样硬化；和(D)一种平滑肌细胞的抑制物 增殖，皂苷，与成纤维细胞生长因子或特异性 针对成纤维细胞生长因子受体的单抗，在 与血小板聚集抑制剂联合使用(例如 血栓素A2和5-羟色胺)显著抑制新生内膜 血管成形术诱导内皮细胞损伤后的增殖。