ANGIOTENSIN II EFFECTS ON CARDIAC FIBROSIS

描述（改编自申请人的摘要）：总体 这些研究的目的是确定 心脏间肾素-血管紧张素系统、纤连蛋白表达 以及与心脏肥大相关的纤维化。 该提案 主要集中在了解影响因素， 心脏纤维化的发展过程中的心脏 慢性暴露于血管紧张素II诱导的肥大。 一个基本 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，其反过来具有 在心脏重塑过程中的功能作用 纤维化 将在完整大鼠中建立实验模型 其中血管紧张素II通过渗透微泵输注以诱导心脏 肥大和纤维化，以及心脏的变化将被记录 使用组织学和生物化学技术。 具体目标 包括：1）表征纤维连接蛋白的时间变化 表达和纤维化，发生在慢性输注 使用生物化学、形态测量和生理学的血管紧张素II 技术; 2）确定纤连蛋白表达的变化是否是 继发于血流动力学变化或由于以下因素的直接影响 使用抗高血压药物或药物对心脏细胞类型的激动剂 影响一氧化氮产生，与升压或 降压剂量的血管紧张素II; 3）使用原位杂交， 测量被认为具有生物学活性的选定生长因子的表达， 自分泌或旁分泌在介导血管紧张素II诱导的 变化，主要集中在血管紧张素 II、TGF-β 1和纤连蛋白; 4）利用来自 新生大鼠心脏，以确定添加的血管紧张素II和 单独或联合TGF-β对纤连蛋白表达和细胞增殖的影响 增殖，检测血管紧张素II诱导的TGF-β， 可能的自分泌回路，并研究可能的相互关系， 血管紧张素II和一氧化氮对这些参数的影响; 启动旨在确定细胞内信号传导的研究 促进血管紧张素II对心脏 成纤维细胞

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.