Angiotensin converting enzyme, angiotensin II, and arrhythmia

描述(由申请人提供)：肾素-血管紧张素系统(RAS)的激活与心血管死亡的增加有关。这个系统的一个关键组成部分是血管紧张素转换酶(ACE)，它将血管紧张素I分解为血管紧张素II(Ang11)。在人类中，血管紧张素转换酶水平升高与室性心律失常风险增加有关。然而，风险增加的原因尚不清楚。RAS激活的一个关键作用是Ang11诱导的氧化应激，部分是通过增加NADPH氧化酶的活性来介导的。我们假设由Ang11引起的氧化应激导致心律失常。为了研究这一点，我们开发了一种心脏受限的ACE过度表达小鼠(ACE 8/8)，该小鼠在没有心力衰竭或结构性心脏病的情况下猝死的风险增加。心内记录显示传导不良和各种形式的房室结传导阻滞。心室起搏易诱发室性心动过速。这种表型与心脏钠通道的减少有关。我们已经开发出初步数据表明，Ang11介导的氧化应激激活转录因子NFkB，导致心脏钠通道下调。在这个提议中，我们假设Ang11增加导致氧化应激，氧化应激反过来通过NFkB激活改变钠通道转录。离子通道水平的改变有助于ACE 8/8小鼠心律失常的表型。这项提案是一项计划，旨在剖析这一假定级联中的步骤，并确定哪些是直接原因，哪些是上游事件，以及哪些是相关但不是原因的步骤。在每个目标中，我们将确定钠通道、NFkB激活、氧化应激和心律失常风险的测量在多大程度上被拟议的信号级联中的干扰所改变。具体目标。具体目标1：确定在我们的ACE过表达模型中，Ang11介导的信号在多大程度上负责钠通道的调节。具体目标2：确定在我们的ACE过表达模型中，NADPH氧化酶的激活在多大程度上负责钠通道的调节。具体目标3：确定在我们的ACE过度表达模型中，NFkB激活增加在多大程度上负责钠通道的调节。这一应用提出了一种新的假说，即为什么RAS激活会导致心律失常，从而导致房颤(AF)和心力衰竭(HF)相关性猝死。

DESCRIPTION (provided by applicant): Activation of the renin-angiotensin system (RAS) is associated with increased cardiovascular death. A critical component of this system is angiotensin converting enzyme (ACE), which cleaves angiotensin I to angiotensin II (Angll). In humans, increased Angll levels are associated with an increased ventricular arrhythmic risk. Nevertheless, the reasons for the increased risk are unclear. One critical effect of RAS activation is Angll-induced oxidative stress mediated, in part, by increased NADPH oxidase activity. We hypothesized that oxidative stress caused by Angll induced cardiac arrhythmias. To investigate this, we developed a cardiac-restricted ACE overexpression mouse (ACE 8/8) that showed an increased risk of sudden death in the absence of heart failure or structural heart disease. Intracardiac recordings demonstrate poor conduction and various forms of AV nodal block. Ventricular pacing readily induced ventricular tachycardia. This phenotype is associated with reductions in cardiac sodium channels. We have developed preliminary data that Angll-mediated oxidative stress activates the transcription factor NFkB resulting in downregulation of the cardiac sodium channel. In this proposal, we hypothesize that increased Angll leads to oxidative stress which in-turn alters sodium channel transcription through NFkB activation. An altered ion channel level contributes to the ACE 8/8 mouse arrhythmic phenotype. This proposal is a plan to dissect the steps in this putative cascade and to identify which are proximate causes, which are upstream events, and which are associated but not causative steps. In each aim, we will establish to what extent measures of the sodium channel, NFkB activation, oxidative stress, and arrhythmic risk are altered by the disruptions in the proposed signaling cascade. Specific Objectives. Specific aim 1: To establish to what extent Angll-mediated signaling is responsible for the sodium channel regulation in our ACE overexpression model. Specific aim 2: To establish to what extent NADPH oxidase activation is responsible for the sodium channel regulation in our ACE overexpression model. Specific aim 3: To establish to what extent increased NFkB activation is responsible for the sodium channel regulation in our ACE overexpression model. This application presents a novel hypothesis about why RAS activation causes arrhythmias, contributing to atrial fibrillation (AF) and heart failure (HF)-associated sudden death.