Renin angiotensin system and connexin43

肾素血管紧张素系统和连接蛋白43

• 批准号: 8391611
• 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/8391611
• 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; public health relevance; 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.

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增加相关。该系统的关键组分是血管紧张素转换酶（ACE），其切割十肽血管紧张素I，产生八氨基酸肽血管紧张素II（AngII），其是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有关，使用ACE抑制剂可降低该风险。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风险增加。在本申请中，我们表明AngII介导的氧化应激通过H2 O2产生激活转录因子NFkB，c-Src在我们的模型中转录上调，并且ACE小鼠在mRNA丰度没有变化的情况下具有减少的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血管紧张素转换酶表型。这将在四个目标中进行测试。在每个目标中，我们将确定氧化应激，NFB，c-Src，Cx43和药物风险的测量在多大程度上被提议的信号级联中的中断所改变。目的是测试一个特定的，合理的信号级联，同时建立级联中间体的顺序。具体目标1：在我们的ACE过表达模型中，确定AngII介导的信号传导在多大程度上负责Cx43调节。具体目标2：在我们的ACE过表达模型中，确定NADPH氧化酶激活在多大程度上负责Cx43调节。具体目标3：在我们的ACE过表达模型中，确定NF κ B激活增加到何种程度负责Cx43调节。具体目标4：确定在我们的ACE过表达模型中，c-Src上调在多大程度上负责Cx43的调节。