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: 8476257
• 负责人: Yanfang Chen
• 金额: $ 34.38万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8476257
• 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.

描述（由申请人提供）：缺血性卒中是美国第三大死亡原因。缺血性中风后减少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）、血管紧张素Ⅱ（Ang Ⅱ）和血管紧张素AT 1受体参与了包括高血压和中风在内的多种心血管疾病的病理生理过程。随着血管紧张素转换酶2（ACE 2）、血管紧张素（1-7）和Mas受体的发现，越来越多的证据表明ACE 2/Ang（1-7）/Mas轴与ACE/Ang II/AT 1轴相互抵消，共同调控血压和血流。然而，这些抵消轴在缺血性卒中中的作用在很大程度上是未知的。活性氧（Reactive oxygen species，ROS）是引起缺血性损伤的重要因素。来自内皮型一氧化氮合酶（eNOS）的一氧化氮（NO）在维持正常脑血流中是重要的。ACE/Ang II/AT 1轴的激活可诱导NADPH氧化酶（NOX）源性ROS的过度产生和eNOS源性NO的减少。最近的研究表明，Ang（1-7）/Mas负性调节人内皮细胞中Ang II/AT 1激活的NADPH氧化酶。有证据表明，ACE/Ang II/AT 1轴的激活通过血流依赖性和非血流依赖性机制参与缺血性卒中的发生。骨髓来源的内皮祖细胞（endothelial progenitor cells，EPCs）和缺血诱导的缺氧诱导因子-1（hypoxia induced factor-1，HIF-1）、基质衍生因子-1a（stromal derived factor-1a，SDF-1a）及其受体CXCR 4表达上调参与缺血性脑卒中后的修复过程（血管生成和神经发生）。综上所述，我们推测ACE 2/Ang（1-7）/Mas轴通过调节NOX/ROS、eNOS/NO和HIF-1/SDF-1a/CXCR 4信号通路，抵消ACE/Ang II/AT 1对神经、脑血管和EPCs功能的调控，从而在脑缺血损伤和修复中发挥重要作用。为了验证这一假设，有转基因小鼠模型，R+A+（肾素和血管紧张素原过度表达），ACE 2 +（ACE 2在脑中过表达）和R+A+ ACE 2 +（ACE 2在R+A+小鼠的脑中过表达）和过表达ACE 2的慢病毒载体（lenti-ACE 2）将用于使用各种整合的生理学、药理学和分子方法追求四个特定目标：具体目标1将通过调节血压和脑血流量来检测ACE 2/Ang（1-7）/Mas在缺血性损伤中对抗ACE/Ang II/AT 1的作用。具体目标2将研究ACE 2/Ang（1-7）/Mas通过独立于血压和脑血流的机制在对抗缺血性损伤中的ACE/Ang II/AT 1中的作用。具体目标3将研究ACE 2/Ang（1-7）/Mas在缺血性卒中后脑修复中对抗ACE/Ang II/AT 1的作用。具体目标4将研究ACE 2/Ang（1-7）/Mas在抵消ACE/Ang II/AT 1在EPCs移植促进缺血性卒中后修复的功效中的作用。

项目成果

The Role of Circulating Platelets Microparticles and Platelet Parameters in Acute Ischemic Stroke Patients.

• DOI: 10.1016/j.jstrokecerebrovasdis.2015.06.018
• 发表时间: 2015-10
• 期刊: Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
• 作者: Chen Y;Xiao Y;Lin Z;Xiao X;He C;Bihl JC;Zhao B;Ma X;Chen Y
• 通讯作者: Chen Y

Angiotensin-(1-7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways.

血管紧张素-(1-7) 通过调节 Nox2/ROS 和 PI3K/NO 途径抵消血管紧张素 II 诱导的脑内皮细胞功能障碍。

• DOI: 10.1016/j.yexcr.2015.06.010
• 发表时间: 2015-08-01
• 期刊: Experimental cell research
• 影响因子: 3.7
• 作者: Xiao X;Zhang C;Ma X;Miao H;Wang J;Liu L;Chen S;Zeng R;Chen Y;Bihl JC
• 通讯作者: Bihl JC

Hypoxia/Aglycemia-induced endothelial barrier dysfunction and tight junction protein downregulation can be ameliorated by citicoline.

胞二磷胆碱可以改善缺氧/血糖引起的内皮屏障功能障碍和紧密连接蛋白下调

• DOI: 10.1371/journal.pone.0082604
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ma X;Zhang H;Pan Q;Zhao Y;Chen J;Zhao B;Chen Y
• 通讯作者: Chen Y

Human endometrial stromal stem cells differentiate into megakaryocytes with the ability to produce functional platelets.

• DOI: 10.1371/journal.pone.0044300
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wang J;Chen S;Zhang C;Stegeman S;Pfaff-Amesse T;Zhang Y;Zhang W;Amesse L;Chen Y
• 通讯作者: Chen Y

Effects of endothelial progenitor cell-derived microvesicles on hypoxia/reoxygenation-induced endothelial dysfunction and apoptosis.

内皮祖细胞来源的微泡对缺氧/复氧诱导的内皮功能障碍和细胞凋亡的影响

• DOI: 10.1155/2013/572729
• 发表时间: 2013
• 期刊: Oxidative medicine and cellular longevity
• 作者: Wang J;Chen S;Ma X;Cheng C;Xiao X;Chen J;Liu S;Zhao B;Chen Y
• 通讯作者: Chen Y