Brain-targeted ACE2 over-expression on angiotensin-II-mediated hypertension

血管紧张素 II 介导的高血压脑靶向 ACE2 过表达

• 批准号: 7900354
• 负责人: ERIC D LAZARTIGUES
• 金额: $ 35.5万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900354
• 关键词: AGTR2 gene; Acute; Address; Angiopoietin-2; Angiotensin II; Arts; Baroreflex; Binding; Blood Pressure; Brain; Brain region; Buffers; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cell Nucleus; Cells; Cessation of life; Chromosome Mapping; Chronic; Collaborations; Conscious; Data; Development; Diabetic Nephropathy; Disease; Dose; Elements; Enzymes; Experimental Models; Face; G alpha q Protein; Generations; Genes; Genetic; Genetically Engineered Mouse; Genomics; Hand; Health; Heart; Heart Hypertrophy; Hypertension; Inbred SHR Rats; Individual; Infusion procedures; Iowa; Kidney; Knockout Mice; Lead; Lesion; Maintenance; Mediating; Medical; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Myocardial Infarction; Names; Neuraxis; Neurons; Nitric Oxide; Nitric Oxide Synthase; Organ; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Peptides; Peptidyl-Dipeptidase A; Phospholipase C; Phosphorylation; Physiological; Play; Prevalence; Prevention; Proteins; Psychological reinforcement; Public Health; Quantitative Trait Loci; Ras/Raf; Reactive Oxygen Species; Receptor Signaling; Regulatory Pathway; Relative (related person); Renal function; Renin-Angiotensin System; Research; Role; Science; Signal Pathway; Signal Transduction; Subfornical Organ; System; Telemetry; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Universities; Vasodilator Agents; World Health Organization; angiotensin I (1-7); attenuation; blood pressure regulation; hypertension treatment; in vivo; member; mouse model; neurogenic hypertension; normotensive; novel therapeutic intervention; novel therapeutics; overexpression; prevent; public health relevance; receptor; response; statistics; tool

DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) is a major regulator of cardiovascular (CV) and renal function in health and disease. Elevated activity and expression of RAS components in central CV control regions and attenuation of the Hypertension with central lesions or administration of angiotensin-II (Ang-II) antagonists have supported the notion that a hyper-functioning brain RAS may be involved in the pathogenesis of Hypertension in several genetic and experimental models. Until now, the common assumption was that Ang-II served as the main actor of this system. A new member of the RAS, ACE2 (angiotensin converting enzyme type 2) has been identified in organs and tissues related to CV function (e.g. heart, kidney, vessels) and appears to be part of a counter-regulatory pathway buffering the excess of Ang-II. We recently identified the ACE2 protein in brain regions involved in the central regulation of blood pressure (BP) and showed that it is regulated by other components of the RAS. In addition, we recently observed that ACE2 over-expression in the subfornical organ (SFO) dramatically reduces the pressor response to central administration of Ang-II in mice and reduces oxidative stress in cells. These observations added to the role of ACE2 in the generation of biologically active peptides like Ang-(1-7), supply a rationale for further explorations in the brain in the face of normal and pathophysiological states. In this proposal, we hypothesize that central ACE2 plays a major compensatory role during Hypertension; ACE2 over-expression will promote Ang-(1-7) formation and Ang-II degradation, resulting in the reinforcement of compensatory mechanisms and preventing Hypertension and the associated oxidative stress. Taking advantage of our expertise in physiological genomics, a science that studies the physiological consequences of gene manipulation, combined to state of the art recording and analysis of CV function in conscious mice, we propose to investigate the consequences of chronic ACE2 over-expression on the development of neurogenic Hypertension. Using a new genetically-engineered mouse model, with brain-targeted ACE2 over- expression, we will: 1) Establish the functional consequences of brain-targeted ACE2 over-expression in neurogenic hypertension. 2) Identify the role of the SFO and RVLM in the ACE2-mediated reduction of Hypertension in Syn- ACE2 transgenic mice and the molecular consequences of their activation. 3) Determine the effects of ACE2 over-expression on Ang-II and Ang-(1-7) receptors signaling pathways. We believe that this unique model will allow us to determine the physiological role of central ACE2 in- vivo in neurogenic Hypertension. Evidence of a beneficial role of ACE2 in BP regulation could lead to the development of new therapeutics as well as a better utilization of existing therapeutics for the treatment of Hypertension and other CV diseases. PUBLIC HEALTH RELEVANCE: Among cardiovascular diseases, worldwide prevalence estimates for Hypertension may be as much as 1 billion individuals, and approximately 7.1 million deaths per year may be attributable to Hypertension. Using transgenic mice, this application will describe the ability of a new enzyme, ACE2, to prevent the development of Hypertension. If confirmed, ACE2 could become a new target for the treatment of Hypertension and other cardiovascular diseases.

描述（由申请人提供）：肾素-血管紧张素系统（RAS）是健康和疾病中心血管（CV）和肾功能的主要调节剂。中央CV控制区RAS成分的活性和表达升高以及中央病变或血管紧张素II（Ang-II）拮抗剂给药后高血压的减轻，支持了这样的观点，即在多种遗传和实验模型中，功能亢进的大脑RAS可能参与了高血压的发病机制。到目前为止，普遍的假设是 Ang-II 是该系统的主要参与者。 RAS 的新成员 ACE2（2 型血管紧张素转换酶）已在与 CV 功能相关的器官和组织（例如心脏、肾脏、血管）中被发现，并且似乎是缓冲过量 Ang-II 的反调节途径的一部分。我们最近在参与血压 (BP) 中枢调节的大脑区域中发现了 ACE2 蛋白，并表明它受到 RAS 的其他成分的调节。此外，我们最近观察到，穹窿下器官（SFO）中 ACE2 的过度表达显着降低了小鼠对中枢给药 Ang-II 的升压反应，并减少了细胞的氧化应激。这些观察结果增加了 ACE2 在 Ang-(1-7) 等生物活性肽生成中的作用，为进一步探索大脑面对正常和病理生理状态提供了理论基础。在这个提议中，我们假设中枢 ACE2 在高血压期间发挥着主要的代偿作用； ACE2 过度表达将促进 Ang-(1-7) 形成和 Ang-II 降解，从而加强代偿机制并预防高血压和相关的氧化应激。利用我们在生理基因组学（一门研究基因操作生理后果的科学）方面的专业知识，结合最先进的记录和分析清醒小鼠的 CV 功能，我们建议研究慢性 ACE2 过度表达对神经源性高血压发展的影响。使用一种新的基因工程小鼠模型，具有脑靶向 ACE2 过度表达，我们将： 1) 确定脑靶向 ACE2 过度表达在神经源性高血压中的功能后果。 2)确定SFO和RVLM在ACE2介导的Syn-ACE2转基因小鼠高血压降低中的作用及其激活的分子后果。 3)确定ACE2过表达对Ang-II和Ang-(1-7)受体信号通路的影响。我们相信，这种独特的模型将使我们能够确定中枢 ACE2 在体内神经源性高血压中的生理作用。 ACE2 在血压调节中的有益作用的证据可能会导致新疗法的开发以及更好地利用现有疗法来治疗高血压和其他心血管疾病。公共卫生相关性：在心血管疾病中，全球高血压患病率估计可能高达 10 亿人，每年约有 710 万人死于高血压。该应用将使用转基因小鼠来描述一种新酶 ACE2 预防高血压发展的能力。如果得到证实，ACE2可能成为治疗高血压和其他心血管疾病的新靶点。