Angiotensin II, Aldosterone, Oxidation, and CaMKII in Hypertrophy and Arrhythmias

血管紧张素 II、醛固酮、氧化和 CaMKII 在肥厚和心律失常中的作用

• 批准号: 7279137
• 负责人: MARK E ANDERSON
• 金额: $ 35.81万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-23 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7279137
• 关键词: Adrenergic Receptor; Aldosterone; Amino Acids; Angiotensin II; Angiotensins; Apoptosis; Apoptotic; Appendix; Arrhythmia; Automobile Driving; Buffers; Calcium/calmodulin-dependent protein kinase; Calmodulin; Cardiac; Cardiac Myocytes; Cessation of life; Complement; Condition; Data; Disease; Dominant-Negative Mutation; Exhibits; Figs - dietary; Functional disorder; Hand; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Histone Deacetylase; Hypertrophy; In Vitro; Infusion procedures; Knowledge; Laboratories; Link; Measures; Methods; Modification; Molecular; Multienzyme Complexes; Mus; Mutagenesis; Myocardial; Myocardial Infarction; NADPH Oxidase; NF-kappa B; Nodal; Outcome; Oxidants; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Proteins; Proteomics; Reactive Oxygen Species; Reagent; Receptor Signaling; Renin; Reporter; Repression; Research Personnel; Role; Signal Pathway; Signal Transduction; Source; Stress; Testing; United States; Work; calmodulin-dependent protein kinase II; clinical phenotype; improved functioning; in vivo; inhibitor/antagonist; innovation; mouse model; mouse p47; novel; oxidation; prevent; programs; research study; response; transcription factor

DESCRIPTION (provided by applicant): Heart failure and arrhythmias are among the most significant causes of premature death in the United States. Activation of renin-angiotensin (Angll)-aldosterone (Aldo) signaling (RAAS) is a common feature of structural heart disease that leads to heart failure and is associated with arrhythmias. Drugs that inhibit RAAS are cornerstones for reducing death in heart failure patients, but the specific 'downstream' cellular signals that are activated by RAAS and represent the proximate cause of adverse structural and pro- arrhythmic electrical remodeling in heart failure are incompletely understood. RAAS causes increased oxidant stress and may increase cellular Ca2+. Our group has found that RAAS causes increased activity of the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) and that CaMKII inhibition prevents or significantly reduces cardiac hypertrophy during RAAS. CaMKII has recently emerged as a pathological signal in heart failure and arrhythmias, and these findings mark CaMKII as a previously unrecognized but necessary signal for pathological RAAS. We have developed evidence that RAAS can activate CaMKII by cellular Ca2+ mobilization (a conventional mechanism) and by a novel, previously unidentified mechanism involving oxidant modification of susceptible amino acid residues in the CaMKII regulatory domain. NADPH oxidase is an enzyme complex that generates reactive oxygen species (ROS) during RAAS, and our preliminary findings suggest that NADPH oxidase is required for maximal CaMKII activity during RAAS. We will answer key questions posed in response to these preliminary findings using the following Specific Aims: 1. Determine the mechanism for CaMKII activation by Angll 2. Determine the role of Angll signaling through NF-kB and MEF2 3. Determine the role of CaMKII in Aldo signaling. The proposed studies will provide critically needed new knowledge of the mechanistic links between RAAS and important clinical phenotypes of cardiac hypertrophy, dysfunction and arrhythmias.

描述（由申请人提供）：心力衰竭和心律失常是美国过早死亡的最重要原因之一。肾素-血管紧张素(Angll)-醛固酮（Aldo）信号（RAAS）的激活是导致心力衰竭并与心律失常相关的结构性心脏病的共同特征。抑制RAAS的药物是降低心力衰竭患者死亡率的基础，但由RAAS激活的特定“下游”细胞信号并代表心力衰竭中不良结构和心律失常前电重构的直接原因尚不完全清楚。RAAS引起氧化应激增加，并可能增加细胞Ca2+。我们的研究小组发现，RAAS导致多功能Ca2+/钙调素依赖性蛋白激酶II （CaMKII）的活性增加，CaMKII抑制可以防止或显著减少RAAS期间的心脏肥厚。CaMKII最近作为心衰和心律失常的病理信号出现，这些发现表明CaMKII是病理性RAAS的一个以前未被认识但必要的信号。我们已经开发的证据表明，RAAS可以激活CaMKII通过细胞Ca2+动员（一种常规机制）和一个新的，以前未知的机制，涉及氧化修饰的易感氨基酸残基在CaMKII调节域。NADPH氧化酶是一种在RAAS过程中产生活性氧（ROS）的酶复合物，我们的初步研究结果表明，在RAAS过程中，NADPH氧化酶是最大化CaMKII活性所必需的。我们将使用以下具体目标回答针对这些初步调查结果提出的关键问题：确定Angll 2激活CaMKII的机制。通过NF-kB和mef3确定Angll信号的作用。确定CaMKII在Aldo信号传导中的作用。拟议的研究将为RAAS与心脏肥厚、功能障碍和心律失常的重要临床表型之间的机制联系提供急需的新知识。