ANGIOTENSIN II EFFECTS ON CARDIAC FIBROSIS

血管紧张素 II 对心脏纤维化的影响

• 批准号: 2702267
• 负责人: PETER I BRECHER
• 金额: $ 24.23万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2702267
• 关键词: angiotensin II; fibroblasts; fibronectins; heart enlargement; in situ hybridization; laboratory rat; model design /development; renin angiotensin system; transforming growth factors

DESCRIPTION (adapted from the applicant's abstract): The overall objective of these studies is to determine the inter-relationships in the heart between the renin-angiotensin system, fibronectin expression and the fibrosis associated with cardiac hypertrophy. The proposal is focused primarily on understanding the factors that influence the development of cardiac fibrosis during the progression of cardiac hypertrophy induced by chronic exposure to angiotensin II. A basic premise is that angiotensin II acts directly on cardiac cell types to induce growth factor and fibronectin expression, which in turn has a functional role in the remodeling processes associated with cardiac fibrosis. An experimental model will be developed in the intact rat where angiotensin II is infused by osmotic minipump to induce cardiac hypertrophy and fibrosis, and changes in the heart will be documented using histological and biochemical techniques. The specific aims include: 1) characterization of the temporal changes in fibronectin expression and fibrosis that occur during the chronic infusion of angiotensin II using biochemical, morphometric and physiological techniques; 2) to determine if changes in fibronectin expression are secondary to hemodynamic changes or are due to direct effects of agonists on cardiac cell types using antihypertensive drugs, or drugs that influence nitric oxide production, in conjunction with pressor or subpressor doses of angiotensin II; 3) to use in situ hybridization to measure the expression of selected growth factors thought to have an autocrine or paracrine role in mediating the angiotensin II induced changes, focusing mainly on the inter-relationships between angiotensin II, TGF-b1 and fibronectin; 4) to utilize cultured fibroblasts from neonatal rat hearts to determine the effects of added angiotensin II and TGF-b alone or in combination on fibronectin expression and cell proliferation, to test for TGF-b induction by angiotensin II as a possible autocrine loop, and to study the possible inter-relationships between angiotensin II and nitric oxide on these parameters; and to initiate studies designed to determine the intracellular signalling pathway that facilitates the effects of angiotensin II on cardiac fibroblasts.

描述（根据申请人的摘要改编）：总体 这些研究的目的是确定相互关系 肾素 - 血管紧张素系统，纤连蛋白表达之间的心脏 以及与心脏肥大相关的纤维化。 该提议是 主要集中于理解影响的因素 心脏进展过程中心脏纤维化的发展 长期暴露于血管紧张素II引起的肥大。 基本 前提是血管紧张素II直接作用于心脏细胞类型 诱导生长因子和纤连蛋白表达，而这又有 与心脏相关的重塑过程中的功能作用 纤维化。 完整的大鼠将开发实验模型 血管紧张素II被渗透微型蛋白酶注入以诱导心脏 肥大和纤维化，心脏的变化将记录在案 使用组织学和生化技术。 具体目标 包括：1）纤连蛋白的时间变化的表征 慢性输注期间发生的表达和纤维化 血管紧张素II使用生化，形态计量学和生理学 技术； 2）确定纤连蛋白表达的变化是否是 继发于血液动力学变化，或者是由于 使用降压药或药物的心脏细胞类型的激动剂 这会影响一氧化氮的产生，并与施加或 血管紧张素II的亚压剂量； 3）用于原位杂交 测量所选生长因子的表达 自分泌或旁分泌在介导血管紧张素II诱导的作用 变化，主要集中于血管紧张素之间的相互关系 II，TGF-B1和纤连蛋白； 4）利用培养的成纤维细胞 新生大鼠心脏确定添加血管紧张素II和 单独的TGF-B或结合纤连蛋白表达和细胞组合 增殖，以血管紧张素II作为A的TGF-B诱导测试TGF-B诱导 可能的自分泌循环，并研究可能的相互关系 在这些参数上，血管紧张素II和一氧化氮之间；然后 启动研究旨在确定细胞内信号传导 促进血管紧张素II对心脏影响的途径 成纤维细胞。