The Renin-Ang II System in Cardiovascular Remodeling

Renin-Ang II 系统在心血管重塑中的作用

• 批准号: 6874298
• 负责人: KATHLEEN HELEN BERECEK
• 金额: $ 32.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874298
• 关键词: ACE inhibitors; RNase protection assay; angiotensin /renin /aldosterone hypertension; angiotensin II; angiotensin receptor; bradykinin; cardiovascular disorder prevention; cardiovascular pharmacology; collagen; echocardiography; fibroblasts; fibrosis; growth factor receptors; hydralazine; laboratory rat; northern blottings; pathologic process; protein biosynthesis; renin angiotensin system; tissue /cell culture; transforming growth factors; western blottings

DESCRIPTION (provided by applicant): The major goal of our studies is to identify the molecular mechanisms underlying the role of Ang II in the development and progression of cardiac fibrosis in the spontaneously hypertensive rat (SHR). An additional goal is to determine the mechanisms underlying the ability of early, short-term application of angiotensin-converting enzyme inhibitors (ACEI) to prevent the development and progression of fibrosis. We have previously found that early, short-term CAP treatment of SHR prevents cardiac fibrosis and may do this by inhibiting the initiation of a pro-fibrotic environment prior to an increase in BP in SHR. This proposal has 3 specific aims: (1) To determine whether early, short-term treatment of SHR with CAP prevents LV remodeling through prolonged blockade of cardiac RAS and whether or not this effect is independent of blood pressure effects. Cardiac function will be monitored by echocardiography, ex vivo perfusion, and hemodynamic studies. Collagen content, distribution, phenotype, and cross-linking will be determined by a combination of biochemical, morphometric, molecular, biological, and Western blot analyses. Ang II and TGF-beta and its receptors will be monitored by biochemical and molecular biological methods. (2) To determine the cellular and molecular mechanisms underlying Ang II-induced cardiac fibrosis in SHR and how they are inhibited by early, short-term CAP. Expression of collagen isoforms and proteins that regulate collagen synthesis (Ang II receptors, TGF-beta) and proteins that regulate collagen degradation (TIMPs, PAl-l) will be determined by RNase protection assays, and Northern and Western blot analyses. (3) To identify the cellular signal transduction cascades in cardiac fibroblasts that mediate the development of cardiac fibrosis by RAS in hypertension. Signaling intermediates will be determined by Western blot analyses. This proposal will utilize SHR, a well-characterized model of genetic hypertension, and it is the first to study Ang II-dependent mechanisms of collagen synthesis and degradation in vivo and in vitro in cardiac fibroblasts, how they change over time, and how they correlate to cardiac function in SHR. These studies will allow us to identify new targets for pharmacological intervention to prevent adverse cardiovascular remodeling in hypertension.

描述（申请人提供）：我们研究的主要目的是确定血管紧张素II在自发性高血压大鼠（SHR）心脏纤维化发生和进展中作用的分子机制。另一个目标是确定早期短期应用血管紧张素转换酶抑制剂（ACEI）预防纤维化发展和进展的机制。我们以前已经发现，早期，短期CAP治疗SHR防止心脏纤维化，并可能通过抑制在SHR血压升高之前启动促纤维化环境来实现这一点。该建议有3个具体目标：（1）确定是否早期，短期治疗SHR与CAP防止左心室重构通过长期阻断心脏RAS和这种效果是否是独立的血压影响。将通过超声心动图、离体灌注和血流动力学研究监测心脏功能。胶原蛋白含量、分布、表型和交联将通过生物化学、形态测定、分子、生物学和蛋白质印迹分析的组合来确定。将通过生物化学和分子生物学方法监测Ang II和TGF-β及其受体。(2)探讨血管紧张素II诱导SHR心脏纤维化的细胞和分子机制，以及早期短期CAP如何抑制血管紧张素II诱导SHR心脏纤维化。通过RNA酶保护测定以及北方和Western印迹分析来确定胶原蛋白同种型和调节胶原蛋白合成的蛋白质（Ang II受体，TGF-β）以及调节胶原蛋白降解的蛋白质（TIMP，PAI-1）的表达。(3)鉴定心脏成纤维细胞中介导高血压时RAS引起心脏纤维化的细胞信号转导级联。将通过蛋白质印迹分析测定信号传导中间体。这项提案将利用SHR，一个良好的遗传性高血压模型，它是第一个研究血管紧张素II依赖的胶原合成和降解机制在体内和体外心脏成纤维细胞，它们如何随着时间的推移而变化，以及它们如何与SHR的心脏功能。这些研究将使我们能够确定药物干预的新靶点，以预防高血压患者的不良心血管重塑。