Balance of Angiotensin II/Angiotensin (1-1): A Target in Ischemic Stroke

血管紧张素 II/血管紧张素 (1-1) 的平衡：缺血性中风的目标

• 批准号: 8111079
• 负责人: Yanfang Chen
• 金额: $ 36.88万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111079
• 关键词: A Mouse; Acute; Angiopoietin-2; Angiotensin II; Angiotensinogen; Angiotensins; Animal Model; Apoptosis; Biological; Blood Pressure; Blood flow; Bone Marrow; Brain; CXCR4 Receptors; CXCR4 Signaling Pathway; CXCR4 gene; Cardiovascular Diseases; Cardiovascular Physiology; Cause of Death; Cell physiology; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Development; Endothelial Cells; Endothelium; Enzymes; Equilibrium; Functional disorder; Human; Hypertension; Hypoxia; Inflammatory Response; Injury; Ischemia; Ischemic Stroke; Lentivirus Vector; Molecular; NADPH Oxidase; Nitric Oxide; Nitric Oxide Pathway; Nitric Oxide Synthase; Pathway interactions; Peptidyl-Dipeptidase A; Pharmaceutical Preparations; Physiological; Play; Process; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Recovery; Recruitment Activity; Renin; Renin-Angiotensin System; Reporting; Role; Stem cell transplant; Stem cells; Stroke; Testing; Transgenic Animals; Transgenic Mice; Transgenic Organisms; United States; Up-Regulation; Work; angiogenesis; angiotensin-producing serum enzyme II; arm; blood pressure regulation; cerebrovascular; insight; mouse model; neurogenesis; neuroregulation; new therapeutic target; public health relevance; receptor; repaired; therapeutic target

DESCRIPTION (provided by applicant): Ischemic stroke is the third leading cause of death in the United States. There are limited avenues for reducing cerebral damage and promoting repair after ischemic stroke. The angiotensin (Ang) converting enzyme (ACE), Ang II and Ang AT1 receptor of the renin-angiotensin system (RAS) participate in the pathophysiology of various cardiovascular diseases including hypertension and stroke. With the discovery of the Ang converting enzyme 2 (ACE2), Ang (1-7) and Mas receptor, accumulating evidence suggest that the ACE2/Ang (1-7)/Mas axis counteracts the ACE/Ang II/AT1 axis in control of blood pressure and flow. However, the role of these counteracting axes in ischemic stroke is largely unknown. Reactive oxygen species (ROS) have been recognized as a major factor contributing to ischemic damage. Nitric oxide (NO) from endothelium nitric oxide synthase (eNOS) is important in maintaining normal cerebral blood flow. Activation of ACE/Ang II/AT1 axis has been shown to induce overproduction of NADPH oxidase (NOX) derived ROS and reduction of eNOS derived NO. A recent report shows that Ang (1-7)/Mas negatively modulates Ang II/AT1 activated NADPH oxidase in human endothelial cells. Evidence suggests that activation of ACE/Ang II/AT1 axis worsens ischemic stroke via both blood flow dependent and independent mechanisms. The bone marrow (BM) derived endothelial progenitor cells (EPCs) and ischemia-induced up-regulation of hypoxia induced factor-1 (HIF-1), stromal derived factor-1a (SDF-1a) and its receptor CXCR4 participate in the repair processes (angiogenesis and neurogenesis) after ischemic stroke. Taken together, we hypothesize that the ACE2/Ang (1-7)/Mas axis counteracts ACE/Ang II/AT1 in control of neural, cerebrovascular and EPCs function through modulating NOX/ROS, eNOS/NO and HIF-1/SDF-1a/CXCR4 signaling pathways, thereby playing an important role in cerebral ischemic damage and repair. To test this hypothesis, there transgenic mice models, R+A+ (renin and angiotensinogen over-expression), ACE2+ (ACE2 over-expressed in the brain) and R+A+ACE2+ (ACE2 over-expressed in the brain of R+A+) mice, and a lentiviral vector over-expressing ACE2 (lenti-ACE2) will be used for pursuing four specific aims using a variety of integrated physiological, pharmacological and molecular approaches: Specific Aim 1 will test the role of ACE2/Ang (1-7)/Mas in counteracting ACE/Ang II/AT1 in ischemic damage through regulating blood pressure and cerebral blood flow. Specific Aim 2 will examine the role of ACE2/Ang (1-7)/Mas in counteracting ACE/Ang II/AT1 in ischemic damage through mechanisms independent of blood pressure and cerebral blood flow. Specific Aim 3 will study the role of ACE2/Ang (1-7)/Mas in counteracting ACE/Ang II/AT1 in cerebral repair after ischemic stroke. Specific Aim 4 will investigate the role of ACE2/Ang (1-7)/Mas in counteracting ACE/Ang II/AT1 in the efficacy of EPCs transplantation for promoting repair after ischemic stroke. PUBLIC HEALTH RELEVANCE: Ischemic stroke is the third leading cause of death in the United States. Currently, there are no effective drugs for reducing cerebral damage and promoting repair after ischemic stroke. The renin-angiotensin system (RAS) is a possible therapeutic target for ischemic stroke. There are two arms of RAS, the angiotensin (Ang) converting enzyme (ACE), Ang II and Ang AT1 receptor (ACE/Ang II/AT1 axis) and the Ang converting enzyme 2 (ACE2), Ang (1-7) and Mas receptor (ACE2/Ang (1-7)/Mas receptor axis). This proposal will test the hypothesis that the ACE2/Ang (1- 7)/Mas axis via counteracting the ACE/Ang II/AT1 plays important roles in acute cerebral ischemic damage and repair. The results of this project will provide new insights on the role of Ang II/Ang (1-7) balance in the pathophysiology of ischemic stroke, and thus facilitate the development of novel therapeutic targets for ischemic stroke.

描述（由申请人提供）：缺血性中风是美国第三大死因。减少缺血性中风后脑损伤和促进修复的途径有限。肾素-血管紧张素系统(RAS)的血管紧张素(Ang)转换酶(ACE)、Ang II和Ang AT1受体参与包括高血压和中风在内的多种心血管疾病的病理生理学。随着血管紧张素转化酶 2 (ACE2)、Ang (1-7) 和 Mas 受体的发现，越来越多的证据表明 ACE2/Ang (1-7)/Mas 轴抵消了 ACE/Ang II/AT1 轴的控制血压和流量。然而，这些对抗轴在缺血性中风中的作用很大程度上未知。活性氧（ROS）已被认为是导致缺血性损伤的主要因素。内皮一氧化氮合酶 (eNOS) 产生的一氧化氮 (NO) 对于维持正常的脑血流非常重要。 ACE/Ang II/AT1 轴的激活已被证明可诱导 NADPH 氧化酶 (NOX) 衍生的 ROS 过量产生，并减少 eNOS 衍生的 NO。最近的一份报告表明，Ang (1-7)/Mas 负向调节人内皮细胞中 Ang II/AT1 激活的 NADPH 氧化酶。有证据表明，ACE/Ang II/AT1 轴的激活通过血流依赖和独立机制加剧缺血性中风。骨髓（BM）来源的内皮祖细胞（EPC）和缺血诱导的缺氧诱导因子-1（HIF-1）、基质衍生因子-1a（SDF-1a）及其受体CXCR4上调参与修复缺血性中风后的过程（血管生成和神经发生）。综上所述，我们假设 ACE2/Ang (1-7)/Mas 轴通过调节 NOX/ROS、eNOS/NO 和 HIF-1/SDF 来抵消 ACE/Ang II/AT1 控制神经、脑血管和 EPC 的功能。 1a/CXCR4信号通路，从而在脑缺血损伤和修复中发挥重要作用。为了检验这一假设，我们建立了转基因小鼠模型，R+A+（肾素和血管紧张素原过度表达）、ACE2+（ACE2在大脑中过度表达）和R+A+ACE2+（ACE2在R+A+大脑中过度表达） ）小鼠和过表达 ACE2 的慢病毒载体（lenti-ACE2）将用于通过各种综合生理学、药理学和分子方法实现四个特定目标： 特定目标 1将测试ACE2/Ang(1-7)/Mas通过调节血压和脑血流量来抵消ACE/Ang II/AT1在缺血性损伤中的作用。具体目标 2 将检查 ACE2/Ang (1-7)/Mas 通过独立于血压和脑血流的机制抵消缺血性损伤中 ACE/Ang II/AT1 的作用。具体目标 3 将研究 ACE2/Ang (1-7)/Mas 在抵消 ACE/Ang II/AT1 在缺血性中风后脑修复中的作用。具体目标 4 将研究 ACE2/Ang (1-7)/Mas 在抵消 ACE/Ang II/AT1 中 EPC 移植促进缺血性中风后修复的功效中的作用。 公共卫生相关性：缺血性中风是美国第三大死因。目前，尚无有效药物可减轻缺血性中风后脑损伤并促进修复。肾素-血管紧张素系统（RAS）是缺血性中风的可能治疗靶点。 RAS 有两个臂，即血管紧张素 (Ang) 转换酶 (ACE)、Ang II 和 Ang AT1 受体（ACE/Ang II/AT1 轴）以及血管紧张素转换酶 2 (ACE2)、Ang (1-7) 和Mas 受体（ACE2/Ang (1-7)/Mas 受体轴）。该提案将检验ACE2/Ang(1-7)/Mas轴通过抵消ACE/Ang II/AT1在急性脑缺血损伤和修复中发挥重要作用的假设。该项目的结果将为Ang II/Ang (1-7)平衡在缺血性中风病理生理学中的作用提供新的见解，从而促进缺血性中风新治疗靶点的开发。