Renin angiotensin system and connexin43

肾素血管紧张素系统和连接蛋白43

• 批准号: 7931573
• 负责人: SAMUEL C DUDLEY
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931573
• 关键词: Address; Admission activity; American; Amino Acids; Angiotensin I; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Arrhythmia; Ascorbic Acid; Atrial Fibrillation; Biological Availability; Biological Markers; Blood Pressure; Canis familiaris; Cardiac; Cardiovascular system; Cessation of life; Cleaved cell; Clinical; Connexin 43; Connexins; Coronary Artery Bypass; Coupling; Data; Defect; Electric Stimulation; Enzyme Inhibition; Event; Family suidae; Generations; Glutathione Disulfide; Healthcare; Heart; Heart Atrium; Heart Diseases; Heart failure; Hospitals; Human; Hydrogen Peroxide; Hydroxyl Radical; Hypertension; Incidence; Intervention; Ion Channel; Knockout Mice; Lead; Left; Link; Lipid Peroxidation; Measures; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Mus; NADPH Oxidase; Nitric Oxide; Nodal; Oxidation-Reduction; Oxidative Stress; Pathology; Patients; Peptides; Peptidyl-Dipeptidase A; Performance; Pericardial effusion; Peroxonitrite; Phenotype; Postoperative Period; Predisposition; Procedures; Production; Proteins; Pulmonary Edema; Receptor, Angiotensin, Type 1; Regulation; Relapse; Renin-Angiotensin System; Risk; SRC gene; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Solid; Sudden Death; Superoxides; Surface; System; Testing; Tissues; Up-Regulation; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; Veterans; abstracting; activating transcription factor; ascorbate; base; human NOS3 protein; improved; inhibitor/antagonist; insight; mortality; mouse model; nitration; novel; novel diagnostics; novel therapeutic intervention; overexpression; oxidant stress; oxidation; oxidized lipid; prevent; prospective; therapy development; tool; voltage

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.

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。该系统的一个关键组成部分是血管紧张素转换酶 (ACE)，它会裂解十肽血管紧张素 I，产生八个氨基酸肽血管紧张素 II (AngII)，这是 RAS 系统的中心信号分子。在人类中，AngII 水平升高与室性心律失常风险增加相关，而使用 ACE 抑制剂可降低该风险。为了研究 RAS 诱发的心律失常，我们开发了一种心脏受限的 ACE 过表达小鼠，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的风险增加。在此应用中，我们表明 AngII 介导的氧化应激通过产生 H2O2 激活转录因子 NFkB，在我们的模型中 c-Src 转录上调，并且 ACE 小鼠在 mRNA 丰度没有变化的情况下减少了 Cx43 蛋白。因此，我们将测试 AngII 在多大程度上导致氧化应激，进而改变 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因所提议的信号级联中断而改变。目的是测试特定的、合理的信号级联，同时建立级联中中间体的顺序。具体目标 1：确定 AngII 介导的信号传导在多大程度上负责我们的 ACE 过表达模型中的 Cx43 调节。具体目标 2：确定 NADPH 氧化酶激活在多大程度上负责我们的 ACE 过表达模型中的 Cx43 调节。具体目标 3：确定在我们的 ACE 过表达模型中，NFkB 激活的增加在多大程度上负责 Cx43 的调节。具体目标 4：确定 c-Src 上调增加在多大程度上对我们的 ACE 过表达模型中的 Cx43 调节负责。 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 信号传导可减少猝死和非猝死，从而提高死亡率。该项目将解决血管紧张素 II 抑制剂如何降低猝死风险的重要临床问题。这可能会对心脏功能下降的情况下如何引发猝死风险产生新的见解。具体来说，该应用将更全面地了解 AngII 对心脏的促心律失常作用，这可能会导致新的诊断和治疗干预措施。