Oxidative stress in hypertension induced cardiac hypertrophy: RAS system

高血压引起的心脏肥大中的氧化应激：RAS系统

• 批准号: 6843766
• 负责人: Robin L Davisson
• 金额: $ 16.91万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6843766
• 关键词: free radical oxygen; gene targeting; genetically modified animals; heart enlargement; hypertension; laboratory mouse; molecular pathology; oxidative stress; renin angiotensin system; transfection /expression vector

The clinical implications of hypertension stem from multi-system end- organ damage. Among the most significant complications of hypertension is cardiac hypertrophy. The renin-angiotensin system has been implicated both in compensatory cardiac hypertrophy and in the pathogenesis of progressive myocardial dysfunction leading to heart failure. Recently a novel signaling mechanism for angiotensin II (Ang II) involving reactive oxygen species (ROS) has been identified in some cell types, yet the involve of this pathway in cardiomyocyte signaling remains relatively unexplored. Our preliminary evidence suggests that intracellular ROS increases may be critically involved in the hypertrophic program elicited by AngII in cardiomyocytes. This project is designed to address the hypothesis that renin-angiotensin system-dependent over-production of ROS is an important mechanism in the pathogenesis of pressure overload cardiac hypertrophy. We will dissect molecular mechanisms of this novel signaling cascade in cardiac hypertrophy, attempting to identify what ROS are important, exploring the role of NAD(P)H oxidase as a source of AngII-induced ROS generation, and elucidating downstream transcription factor activation. These studies using both in vitro and in vivo model systems, rely on highly selective genetic tools including 1) recombinant adenoviral vectors that encode redox modulating enzymes and dominant- negative inhibitors, and 2) genetically manipulated mouse strains. Our ultimate goal is to develop new therapeutic targets capable of interrupting the evolution from hypertension to hypertrophy to heart failure.

高血压的临床意义源于多系统末端器官损伤。高血压最重要的并发症之一是心脏肥大。肾素 - 血管紧张素系统既涉及补偿性心脏肥大，又是进行性心肌功能障碍的发病机理，导致心力衰竭。最近在某些细胞类型中鉴定出了一种涉及活性氧（ROS）的血管紧张素II（ANG II）的新型信号传导机制，但是该途径在心肌细胞信号传导中的涉及仍然相对尚未探索。我们的初步证据表明，细胞内ROS的增加可能与Angii在心肌细胞中引起的肥厚良好程序有关。该项目旨在解决以下假设：肾素 - 血管紧张素系统依赖性ROS的过度生产是压力过载心脏肥大的发病机理的重要机制。我们将在心脏肥大中剖析这种新型信号传导级联反应的分子机制，试图识别ROS重要的内容，探索NAD（P）H氧化酶作为Angii诱导的ROS产生的来源，并阐明下游转录因子激活。这些研究都使用体外和体内模型系统，依赖于高度选择性的遗传工具，包括1）重组腺病毒载体，编码氧化还原调节酶和显性 - 阴性抑制剂以及2）遗传操纵的小鼠菌株。我们的最终目标是开发能够中断从高血压到肥大到心力衰竭的新治疗靶标。