Oxidative stress in hypertension induced cardiac hypertrophy: RAS system

高血压的临床意义源于多系统终末器官损害。高血压最重要的并发症之一是心肌肥厚。肾素-血管紧张素系统参与了代偿性心肌肥厚和进行性心肌功能障碍导致心力衰竭的发病机制。近年来，在某些细胞类型中发现了一种新的血管紧张素II(Ang II)信号转导机制，但该信号转导途径在心肌细胞信号转导中的作用尚不清楚。我们的初步证据表明，细胞内ROS的增加可能与血管紧张素转换酶诱导的心肌细胞肥大有关。本项目旨在阐明肾素-血管紧张素系统依赖的ROS过度产生是压力超负荷心肌肥厚发病的重要机制的假说。我们将剖析这种新的信号级联在心肌肥厚中的分子机制，试图确定哪些ROS是重要的，探索NAD(P)H氧化酶作为Angii诱导的ROS产生的来源的作用，并阐明下游转录因子的激活。这些研究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)编码氧化还原调节酶和显性负抑制物的重组腺病毒载体，以及2)基因操纵的小鼠品系。我们的最终目标是开发新的治疗靶点，能够阻止从高血压到肥厚再到心力衰竭的演变。

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.