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

描述(申请人提供)：在美国，心力衰竭和心律失常是导致过早死亡的最重要原因。肾素-血管紧张素(Ang11)-醛固酮(ALDO)信号通路的激活(RAAS)是结构性心脏病的常见特征，可导致心力衰竭，并与心律失常相关。抑制RAAS的药物是减少心力衰竭患者死亡的基石，但由RAAS激活并代表心力衰竭不利结构性和促心律失常电重构的特定“下游”细胞信号尚不完全清楚。RAAS导致氧化应激增加，并可能增加细胞内的钙离子。我们的研究小组发现，RAAS导致多功能钙/钙调蛋白依赖性蛋白激酶II(CaMKII)活性增加，抑制CaMKII可防止或显著减轻RAAS期间的心肌肥厚。最近，CaMKII作为心力衰竭和心律失常的病理信号而出现，这些发现标志着CaMKII是一种以前未被识别但对于病理性RAAS来说是必要的信号。我们已经找到证据表明，RAAS可以通过细胞内钙动员(一种传统的机制)和一种新的、先前未知的机制激活CaMKII，该机制涉及对CaMKII调节域中敏感氨基酸残基的氧化修饰。NADPH氧化酶是一种在RAAS过程中产生活性氧物种(ROS)的酶复合体，我们的初步发现表明，RAAS过程中最大的CaMKII活性需要NADPH氧化酶。我们将通过以下具体目标回答针对这些初步发现提出的关键问题：1.确定Ang11激活CaMKII的机制2.通过核因子-kB和MEF2确定Ang11信号的作用3.确定CaMKII在Aldo信号中的作用。拟议的研究将为RAAS和心肌肥厚、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迫切需要的新知识。

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.