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: 2226288
• 负责人: James T. Willerson
• 金额: $ 20.01万
• 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/2226288
• 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.

新生内膜纤维增生是导致新生内膜增生的病理过程， 血管成形术后再狭窄。 病理生理事件导致 新生内膜增生可分为三个阶段：急性期 在对损伤作出反应的起始阶段， 肌肉迁移和增殖，以及慢性永久化阶段 新生内膜增生 这项研究的目的是 阐明新生内膜起始阶段的基本机制， 机械性内皮损伤后的纤维增生 冠状动脉血管成形术的结果， 没有内在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， 球囊血管成形术后新生内膜纤维增生。 细胞 培养组织和慢性仪器犬模型， 没有天然冠状动脉粥样硬化将用于休息， 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， 新生内膜纤维增生的发展;（B）血小板源性 血管活性物质（血栓素A2和血清素）和血管壁- 衍生的血管活性物质（血管紧张素II）协同相互作用 与其他局部产生的生长因子一起启动 冠状动脉粥样硬化性心脏病后发生的新生内膜纤维增生和再狭窄 （c）成纤维细胞生长因子及其受体的作用 在球囊扩张后发生的新生内膜增殖中的作用 血管成形术后，他们增加内皮损伤， 犬冠状动脉成形术 动脉粥样硬化;和（d）平滑肌细胞抑制剂 增殖，皂草素，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克隆抗体， 与血小板聚集的抑制剂（例如血小板聚集的拮抗剂）联合使用， 血栓素A2和血清素）显着减弱新生内膜 血管成形术诱导的内皮损伤后的增殖。