Angiotensin converting enzyme, angiotensin II, and arrhythmia

描述（由申请方提供）：肾素-血管紧张素系统（RAS）激活与心血管死亡增加相关。该系统的关键组分是血管紧张素转化酶（ACE），其将血管紧张素I裂解为血管紧张素II（AngII）。在人类中，增加的AngII水平与增加的心室肥大风险相关。然而，风险增加的原因尚不清楚。RAS激活的一个关键作用是AngII诱导的氧化应激，其部分由增加的NADPH氧化酶活性介导。我们假设由AngII引起的氧化应激诱导心律失常。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。我们已经开发了AngII介导的氧化应激激活转录因子NF κ B导致心脏钠通道下调的初步数据。在该提议中，我们假设增加的AngII导致氧化应激，其进而通过NF κ B活化改变钠通道转录。改变的离子通道水平有助于ACE 8/8小鼠的细胞表型。本提案是一项计划，旨在剖析这一假定级联中的步骤，并确定哪些是近因，哪些是上游事件，哪些是相关但不是因果步骤。在每一个目标中，我们将建立在何种程度上的措施，钠通道，NF κ B激活，氧化应激，并在拟议的信号级联的中断改变了糖尿病风险。具体目标。具体目标1：确定AngII介导的信号传导在何种程度上负责我们的ACE过表达模型中的钠通道调节。具体目标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。具体目标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。本申请提出了一种关于RAS激活导致心律失常的新假设，导致房颤（AF）和心力衰竭（HF）相关猝死。

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.