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增加有关。该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裂解为血管紧张素II （Angll）。在人类中，Angll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angll诱导的氧化应激，部分是由NADPH氧化酶活性增加介导的。我们假设Angll引起的氧化应激引起心律失常。为了研究这一点，我们开发了一种心脏限制性ACE过表达小鼠（ACE 8/8），该小鼠在没有心力衰竭或结构性心脏病的情况下显示猝死风险增加。心内记录显示传导不良和各种形式的房室结阻滞。心室起搏容易引起室性心动过速。这种表型与心脏钠通道的减少有关。我们已经开发了初步数据，angll介导的氧化应激激活转录因子NFkB，导致心脏钠通道下调。在本研究中，我们假设Angll升高导致氧化应激，进而通过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小鼠心律失常表型。这个建议是一个计划，用来剖析这个假定的级联中的步骤，并确定哪些是近因，哪些是上游事件，哪些是相关的但不是因果的步骤。在每个目标中，我们将确定在多大程度上钠通道、NFkB激活、氧化应激和心律失常风险的测量被所提出的信号级联的破坏所改变。具体的目标。具体目的1：在我们的ACE过表达模型中，确定angll介导的信号在多大程度上负责钠通道调节。具体目的2：在我们的ACE过表达模型中，确定NADPH氧化酶激活在多大程度上负责钠通道调节。具体目的3：在我们的ACE过表达模型中，确定NFkB激活增加在多大程度上负责钠通道调节。这个应用提出了一个新的假说，为什么RAS激活会导致心律失常，导致心房颤动（AF）和心力衰竭（HF）相关的猝死。

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.