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（由申请人提供）：我们研究的主要目标是确定ANG II在自发性高血压大鼠（SHR）中心脏纤维化发展和进展中的作用中的分子机制。另一个目标是确定早期，短期应用血管紧张素转化酶抑制剂（ACEI）的能力的机制，以防止纤维化的发展和发展。我们以前已经发现，SHR的早期短期帽治疗可以防止心脏纤维化，并可以通过在SHR中增加BP之前抑制促纤维化环境的启动来做到这一点。该提案具有3个具体目的：（1）确定对SHR用CAP的早期短期治疗是否可以通过长时间对心脏RAS的封锁来防止LV重塑，以及该作用是否与血压效应无关。心脏功能将通过超声心动图，体内灌注和血液动力学研究来监测。胶原蛋白含量，分布，表型和交联将通过生化，形态计量学，分子，生物学和蛋白质印迹分析的组合确定。 ANG II和TGF-β及其受体将通过生化和分子生物学方法来监测。 （2）确定ANG II诱导的SHR中的细胞和分子机制，以及如何通过早期的短期CAP抑制它们。调节胶原蛋白合成的胶原蛋白和蛋白质的表达（ANG II受体，TGF-β）和调节胶原蛋白降解（TIMPS，PAL-L）的蛋白质将通过RNase Prosption Assays，Northern和Western Blot分析确定。 （3）确定心脏成纤维细胞中的细胞信号转导级联，以介导Hypersenion Ras的心脏纤维化发展。信号传导中间体将通过蛋白质印迹分析确定。该提案将利用SHR，这是一种遗传性高血压的特征良好模型，它是第一个研究胶原蛋白合成和体内胶原蛋白合成和降解的机制，并且在心脏成纤维细胞中的体外，它们如何随时间变化以及它们如何相关的心脏功能在SHR中。这些研究将使我们能够确定药理学干预的新靶标，以防止心血管不良重塑高血压。