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: 7146836
• 负责人: MARK E ANDERSON
• 金额: $ 36.88万
• 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/7146836
• 关键词: NAD(P)H dehydrogenase; aldosterone; angiotensin II; arrhythmia; calcium flux; calmodulin dependent protein kinase; enzyme activity; free radical oxygen; genetically modified animals; heart failure; kinase inhibitor; laboratory mouse; nuclear factor kappa beta; oxidative stress; renin angiotensin system; transcription factor; ventricular hypertrophy

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）：心力衰竭和心律不齐是美国早死亡的最重要原因之一。肾素 - 血管紧张素（Angll） - 醛固酮（Aldo）信号传导（RAAS）的激活是结构性心脏病的常见特征，导致心力衰竭，与心律不齐有关。抑制RAAS的药物是减少心力衰竭死亡的基石，但是由RAAS激活并代表了不良结构和心律不足的心力衰竭导致心力衰竭的特定“下游”细胞信号是未完全理解的。 RAA会导致氧化剂应激增加，并可能增加细胞Ca2+。我们的小组发现，RAA会导致多功能Ca2+/钙调蛋白依赖性蛋白激酶II（CAMKII）的活性增加，并且CAMKII抑制可防止或显着降低RAAS期间的心脏肥大。 Camkii最近成为心力衰竭和心律不齐的病理信号，这些发现标志着Camkii作为先前未知但对病理RAA的必要信号。我们已经建立了证据表明，RAA可以通过细胞CA2+动员（一种常规机制）以及一种新型的，未识别的机制来激活CAMKII，该机制涉及CAMKII调节域中易感氨基酸残基的氧化剂修饰。 NADPH氧化酶是一种酶复合物，在RAAS期间产生活性氧（ROS），我们的初步发现表明，NADPH氧化酶是RAAS期间最大CAMKII活性所必需的。我们将使用以下特定目的回答对这些初步发现提出的关键问题：1。确定Angll 2的CAMKII激活机制。确定通过NF-KB和MEF2 3的ANGLL信号的作用。确定CAMKII在Aldo信号中的作用。 拟议的研究将为RAAS与心脏肥大，功能障碍和心律不齐的重要临床表型之间的机械联系提供至关重要的新知识。