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Angiotensin converting enzyme, angiotensin II, and arrhythmia

血管紧张素转换酶、血管紧张素 II 和心律失常

基本信息

批准号：
7645746
负责人：
SAMUEL C DUDLEY
金额：
$ 38.86万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7645746
关键词：
Abbreviations Amino Acids Angiotensin I Angiotensin II Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Angiotensins Arrhythmia Ascorbic Acid Atrial Fibrillation Binding Biochemical Biological Availability Biological Markers Blood Pressure Canis familiaris Cardiac Cardiovascular system Cell Culture System Cell Culture Techniques Cessation of life Cleaved cell Consensus Coronary Artery Bypass Data Defect Down-Regulation EMSA Electric Countershock Electric Stimulation Electrocardiogram Electron Spin Resonance Spectroscopy Electrophoretic Mobility Shift Assay Electrophysiology (science)Enzyme Inhibition Enzymes Event Family suidae Figs - dietary Funding Generations Genes Genetic Transcription Glutathione Disulfide Heart Atrium Heart Diseases Heart failure Human Hydrogen Peroxide Hydroxyl Radical Hypertension Immunoprecipitation Incidence Intervention Ion Channel Knock-out Knockout Mice Left Left atrial structure Left ventricular structure Link Lipid Peroxidation Magnetic Resonance Imaging Measures Mediating Mitogen-Activated Protein Kinase Kinases Modeling Molecular Mus Mutation Myosin Heavy Chains NADP NADPH Oxidase Nitric Oxide Nodal Oxidases Oxidation-Reduction Oxidative Stress Oxygen Pathology Patients Peptides Peptidyl-Dipeptidase A Performance Pericardial effusion Peroxonitrite Phenotype Plasminogen Activator Inhibitor 1 Postoperative Period Predisposition Procedures Production Prostaglandin-Endoperoxide Synthase Protein Kinase Proteins Pulmonary Edema Reactive Oxygen Species Receptor, Angiotensin, Type 1 Reduced Glutathione Regulation Relapse Renin-Angiotensin System Research Personnel Right atrial structure Right ventricular structure Risk Sampling Serum Serum-Free Culture Media Shapes Signal Pathway Signal Transduction Signaling Molecule Site Sodium Channel Sudden Death Superoxide Dismutase Superoxides Surface System Testing Thromboplastin Tissues Tumor Necrosis Factor-alpha Tumor Necrosis Factors Type 2 Angiotensin II Receptor Ventricular Ventricular Arrhythmia Ventricular Tachycardia Xanthine Oxidase activating transcription factor ascorbate auricular appendage base catalase dihydroethidium diphenyleneiodonium egg extracellular fetal guanidine thiocyanate human NOS3 protein inhibitor/antagonist intraperitoneal mouse model nitration novel overexpression oxidant stress oxidation prevent programs promoter prospective receptor tetrahydrobiopterin therapy development tool voltage

项目摘要

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.

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。该系统的一个重要组成部分是血管紧张素转换酶（ACE），它将血管紧张素I切割为血管紧张素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中断改变中毒风险。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。