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脏肥大。肾素-血管紧张素系统与代偿性心肌肥大和导致心力衰竭的进行性心肌功能障碍的发病机制有关。近年来，血管紧张素II（Ang II）信号转导途径中活性氧（ROS）的参与在某些细胞中被发现，但这一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，细胞内活性氧的增加可能是至关重要的参与肥大程序引起的血管紧张素Ⅱ在心肌细胞。本研究旨在探讨肾素-血管紧张素系统依赖性的ROS过度产生是压力超负荷性心肌肥厚发病机制中的一个重要机制。我们将剖析这种新的信号级联在心脏肥大的分子机制，试图确定什么ROS是重要的，探索NAD（P）H氧化酶作为血管紧张素II诱导的ROS产生的来源的作用，并阐明下游转录因子的激活。这些使用体外和体内模型系统的研究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剂的重组腺病毒载体，和2）遗传操作的小鼠品系。我们的最终目标是开发新的治疗靶点，能够中断从高血压到肥大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.