Renin angiotensin system and connexin43

描述(由申请人提供)： 项目摘要。肾素-血管紧张素系统(RAS)的激活与心血管死亡的增加有关。该系统的关键组成部分是血管紧张素转换酶(ACE)，它能分解十肽血管紧张素I，产生RAS系统的中央信号分子血管紧张素II(AngII)。在人类中，血管紧张素转换酶水平的升高与室性心律失常风险的增加有关，而使用ACE抑制剂可以降低这种风险。为了研究RAS诱导的心律失常，我们开发了一种心脏限制性ACE过度表达的小鼠，该小鼠在没有心力衰竭或结构性心脏病的情况下猝死的风险增加。在这个应用中，我们证明了Angii介导的氧化应激通过过氧化氢的产生激活了转录因子NFkB，在我们的模型中c-Src转录上调，并且ACE小鼠在没有mRNA丰度变化的情况下降低了Cx43蛋白。因此，我们将测试Angii在多大程度上导致氧化应激，氧化应激反过来改变Cx43，从而导致ACE 8/8心律失常表型。这将在4个目标中进行测试。在每个目标中，我们将确定氧化应激、NFB、c-Src、Cx43和心律失常风险的测量在多大程度上被拟议的信号级联中的干扰所改变。构建目标是为了测试特定的、可信的信号级联，同时建立级联中中间体的顺序。具体目标1：在我们的ACE过表达模型中，确定Angii介导的信号在多大程度上调控Cx43。具体目的2：确定在我们的ACE过表达模型中，NADPH氧化酶的激活在多大程度上调节Cx43的表达。具体目标3：确定在我们的ACE过表达模型中，NFkB激活增加在多大程度上对Cx43的调控负责。具体目标4：确定在我们的ACE过表达模型中，c-Src上调在多大程度上对Cx43的调控负责。 公共卫生相关性： 对退伍军人医疗保健的潜在影响。心力衰竭是退伍军人和所有美国人入院和死亡的最常见原因之一。抑制心力衰竭中的血管紧张素II信号可以减少猝死和非猝死，从而提高死亡率。这个项目将解决一个重要的临床问题，即血管紧张素II抑制剂如何降低猝死风险。这可能导致对在心脏功能下降的情况下如何产生猝死风险的新见解。具体地说，这一应用将使人们更全面地了解AngII对心脏的促心律失常作用，这可能导致新的诊断和治疗干预措施。

DESCRIPTION (provided by applicant): Project abstract. Activation of the renin-angiotensin system (RAS) system is associated with increased cardiovascular death. A critical component of this system is angiotensin converting enzyme (ACE), which cleaves the decapeptide angiotensin I, producing the eight amino acid peptide angiotensin II (AngII), a central signaling molecule of the RAS system. In humans, increased AngII levels are associated with an increased ventricular arrhythmic risk, and use of ACE inhibitors reduces that risk. To investigate RAS induced arrhythmias, we developed a cardiac-restricted ACE overexpression mouse that shows an increased risk of sudden death in the absence of heart failure or structural heart disease. In this application, we show that AngII- mediated oxidative stress activates the transcription factor NFkB via H2O2 production, c-Src is transcriptionally upregulated in our model, and ACE mice have reduced Cx43 protein in the absence of changes in mRNA abundance. Therefore, we will test to what extent AngII leads to oxidative stress which in-turn alters Cx43, contributing to the ACE 8/8 arrhythmic phenotype. This will be tested in 4 aims. In each aim, we will establish to what extent measures of oxidative stress, NFB, c-Src, Cx43, and arrhythmic risk are altered by the disruptions in the proposed signaling cascade. The aims are constructed to test a specific, plausible signaling cascade and simultaneously establish the order of the intermediates in the cascade. Specific aim 1: To establish to what extent AngII-mediated signaling is responsible for the Cx43 regulation in our ACE overexpression model. Specific aim 2: To establish to what extent NADPH oxidase activation is responsible for the Cx43 regulation in our ACE overexpression model. Specific aim 3: To establish to what extent increased NFkB activation is responsible for the Cx43 regulation in our ACE overexpression model. Specific aim 4: To establish to what extent increased c-Src upregulation is responsible for the Cx43 regulation in our ACE overexpression model. PUBLIC HEALTH RELEVANCE: Potential Impact to Veterans Health Care. Heart failure is one of the most common causes of hospital admission and death in veterans and all Americans. Inhibiting angiotensin II signaling in heart failure has improved mortality by reducing sudden and non-sudden death. This project will address an important clinical problem of how do angiotensin II inhibitors reduce sudden death risk. This is likely to lead to new insights into how sudden death risk is incurred in conditions of reduced cardiac function. Specifically, this application will give a more complete picture of the pro-arrhythmic effects of AngII on heart, which could lead to new diagnostic and therapeutic interventions.