ANGIOTENSIN II EFFECTS ON CARDIAC FIBROSIS

描述(改编自申请人的摘要)：总体情况 这些研究的目的是确定 心脏之间肾素-血管紧张素系统、纤维连接蛋白的表达 与心肌肥厚相关的纤维化。该提案是 主要关注于了解影响 心脏疾病进展过程中心脏纤维化的进展 慢性暴露于血管紧张素所致的肥大II.基础 前提是血管紧张素II直接作用于心肌细胞类型以 诱导生长因子和纤维连接蛋白的表达，进而具有 心脏重构过程中的功能作用 纤维化症。将建立完整大鼠的实验模型 血管紧张素II由渗透压小泵注入诱导心脏 肥大和纤维化，以及心脏的变化将被记录下来 使用组织学和生化技术。具体目标 包括：1)纤维连接蛋白的时间变化特征 在慢性输注过程中发生的表达和纤维化 血管紧张素II的生化、形态计量学和生理学研究 技术；2)确定纤维连接蛋白表达的变化是否 继发于血流动力学改变或由于直接影响 使用抗高血压药物或药物对心肌细胞类型的激动剂 会影响一氧化氮的产生，与增压剂或 血管紧张素II的降压剂；3)使用原位杂交 测量选定的生长因子的表达被认为具有 自分泌或旁分泌在介导血管紧张素II诱导中的作用 变化，主要集中在血管紧张素之间的相互关系 2)转化生长因子-β1和纤维连接蛋白；4)利用培养的成纤维细胞 血管紧张素II和血管紧张素转换酶对新生大鼠心脏的影响 转化生长因子-β单独或联合应用对纤维连接蛋白表达及细胞的影响 增殖，以检测血管紧张素II对转化生长因子-β的诱导作用 可能的自分泌循环，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递的研究 促进血管紧张素II对心脏的影响的途径 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.