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: 8289581
• 负责人: ERIC D LAZARTIGUES
• 金额: $ 35.15万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289581
• 关键词: AGTR2 gene; Acute; Address; Angiotensin II; 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; G alpha q Protein; Generations; Genes; Genetic Models; Genetically Engineered Mouse; Genomics; 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; 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; 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; 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控制区域中RAS成分的活性和表达升高以及中央病变的高血压衰减或血管紧张素II（ANG-II）拮抗剂的拮抗剂支持这样一种观点，即可能涉及过度功能的脑RAS可能参与在几种遗传和实验模型中的高血压。到目前为止，共同的假设是Ang-II是该系统的主要参与者。在与CV功能相关的器官和组织中鉴定了RAS的新成员ACE2（血管紧张素转化2型酶）（例如心脏，肾脏，血管），并且似乎是反调节途径的一部分，可缓冲ANG的过量-ii。我们最近确定了参与血压中心调节（BP）的大脑区域的ACE2蛋白，并表明它受RAS的其他成分调节。此外，我们最近观察到，亚构造器官（SFO）中的ACE2过表达大大降低了小鼠中心对ANG-II中央给药的反应，并减少了细胞中的氧化应激。这些观察结果添加了ACE2在Ang-（1-7）（1-7）（1-7）等生物活性肽产生中的作用，为在正常和病理生理状态下在大脑中进一步探索的基本原理。在该提案中，我们假设中央ACE2在高血压期间起着主要的补偿作用。 ACE2过表达将促进ANG-（1-7）形成和ANG-II降解，从而增强补偿机制并防止高血压和相关的氧化应激。利用我们在生理基因组学方面的专业知识，这是一门研究基因操纵的生理后果的科学，结合了有意识小鼠中CV功能的最新记录和分析，我们建议研究慢性ACE2过表达对慢性ACE 2神经源性高血压的发展。使用新的遗传学工程小鼠模型，具有脑靶向的ACE2过度表达，我们将：1）在神经源性高血压中建立靶向脑靶向大脑的ACE2过表达的功能后果。 2）确定SFO和RVLM在ACE2介导的Syn-ACE2转基因小鼠中高血压的降低以及其激活的分子后果中的作用。 3）确定ACE2过表达对Ang-II和Ang-（1-7）受体信号通路的影响。我们认为，这种独特的模型将使我们能够确定中央ACE2中心在神经源性高血压中的生理作用。 ACE2在BP调节中发挥有益作用的证据可能导致新的治疗剂的发展，并更好地利用现有的治疗疗法来治疗高血压和其他简历疾病。公共卫生相关性：在心血管疾病中，全球高血压的患病率估计值可能高达10亿个人，每年约有710万人死亡可能归因于高血压。使用转基因小鼠，该应用将描述一种新酶ACE2防止高血压发育的能力。如果得到证实，ACE2可能会成为治疗高血压和其他心血管疾病的新目标。