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: 6776058
• 负责人: KATHLEEN HELEN BERECEK
• 金额: $ 35.03万
• 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/6776058
• 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)：我们研究的主要目标是确定Ang II在自发性高血压大鼠(SHR)心脏纤维化的发生和发展中所起作用的分子机制。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)以防止纤维化发生和进展的潜在机制。我们之前已经发现，早期、短期的CAP治疗自发性高血压可以预防心脏纤维化，并且可能通过在自发性高血压患者血压升高之前抑制促纤维化环境的启动来做到这一点。这项建议有三个具体目的：(1)确定早期、短期使用CAP治疗SHR是否通过长时间阻断心脏RAS来防止左室重构，以及这种作用是否独立于血压影响。心功能将通过超声心动图、体外灌流和血流动力学研究进行监测。胶原蛋白的含量、分布、表型和交联性将通过生化、形态计量、分子、生物学和蛋白质印迹分析相结合的方法来确定。血管紧张素II和转化生长因子-β及其受体将通过生化和分子生物学方法进行监测。(2)探讨血管紧张素转换酶II诱导的自发性高血压大鼠心肌纤维化的细胞和分子机制以及早期、短期CAP对其的抑制作用。调节胶原合成的胶原异构体和蛋白(血管紧张素Ⅱ受体，转化生长因子-β)和调节胶原降解的蛋白(TIMPs，PAL-L)的表达将通过核糖核酸酶保护试验以及Northern和Western印迹分析来确定。(3)明确RAS介导高血压心肌纤维化发生的细胞内信号转导通路。信号中间产物将通过蛋白质印迹分析来确定。这项建议将利用SHR，一个具有良好特征的遗传性高血压模型，并首次研究了体内和体外心脏成纤维细胞胶原合成和降解的Ang II依赖机制，它们如何随时间变化，以及它们与SHR心功能的相关性。这些研究将使我们能够确定药物干预的新靶点，以防止高血压患者不利的心血管重构。