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) 心脏纤维化的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）预防纤维化发生和进展的能力的机制。我们之前发现，SHR 的早期、短期 CAP 治疗可以预防心脏纤维化，并且可能通过在 SHR 血压升高之前抑制促纤维化环境的启动来实现这一目的。该提案有 3 个具体目标：(1) 确定早期、短期 SHR 联合 CAP 治疗是否可以通过长期阻断心脏 RAS 来预防左心室重构，以及这种作用是否独立于血压影响。将通过超声心动图、离体灌注和血流动力学研究来监测心脏功能。胶原含量、分布、表型和交联将通过生化、形态测定、分子、生物学和蛋白质印迹分析的组合来确定。将通过生化和分子生物学方法监测Ang II和TGF-β及其受体。 (2) 确定 SHR 中 Ang II 诱导的心脏纤维化的细胞和分子机制以及早期、短期 CAP 如何抑制它们。胶原同工型和调节胶原合成的蛋白质(Ang II受体，TGF-β)和调节胶原降解的蛋白质(TIMP，PA1-1)的表达将通过RNase保护测定以及Northern和Western印迹分析来确定。 (3) 鉴定心脏成纤维细胞中通过RAS介导高血压心脏纤维化发展的细胞信号转导级联。信号中间体将通过蛋白质印迹分析来确定。该提案将利用 SHR（一种具有良好特征的遗传性高血压模型），首次研究心脏成纤维细胞体内和体外胶原蛋白合成和降解的 Ang II 依赖性机制、它们如何随时间变化以及它们如何变化。与 SHR 中的心脏功能相关。这些研究将使我们能够确定药物干预的新目标，以预防高血压引起的不良心血管重塑。