The Renin-Angiotensin II System in Cardiovascular Remodeling

肾素-血管紧张素 II 系统在心血管重塑中的作用

基本信息

批准号：
7225222
负责人：
KATHLEEN HELEN BERECEK
金额：
$ 30.93万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7225222
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Angiopoietin-2 Angiotensin II Angiotensin II Receptor Angiotensin-Converting Enzyme Inhibitors Antihypertensive Agents Biochemical Biological Biological Assay Blood Pressure Bradykinin Receptor Captopril Cardiac Cardiovascular system Chronic Collagen Development Down-Regulation Echocardiography Environment Extracellular Matrix Fibroblasts Fibrosis Generations Genetic Models Goals Heart Hydralazine Hypertension Hypertrophy Hypotension In Vitro Inbred SHR Rats Inbred WKY Rats Intervention Left Ventricular Function Left Ventricular Remodeling Matrix Metalloproteinases Mediating Mediator of activation protein Methods Mitogen-Activated Protein Kinases Molecular Monitor Pathway interactions Peptides Phenotype Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphorylation Plasminogen Activator Inhibitor 1 Prevention Production Protein Isoforms Proteins RNase protection assay Receptor, Angiotensin, Type 1 Regulation Renin Research Personnel Role Signal Pathway Signal Transduction Signaling Molecule Staging System Testing Time Tissues Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transforming Growth Factors Up-Regulation Western Blotting base crosslink ex vivo perfusion familial hypertension genetic inhibitor genetic manipulation hemodynamics human MAPK14 protein in vivo inhibitor/antagonist interest mitogen-activated protein kinase p38 novel pressure prevent programs receptor response treatment effect

项目摘要

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。