Angiotensin-Converting Enzyme2 in Vascular Endothelial Function

血管紧张素转换酶2对血管内皮功能的影响

基本信息

批准号：
8259416
负责人：
MICHAEL J KATOVICH
金额：
$ 54.26万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8259416
关键词：
Acute Lung Injury Angiopoietin-2 Angiotensin II Angiotensins Animal Model Animals Attenuated Blood Vessels Cardiac Cell Therapy Cells Cessation of life Clinical Clinical Trials Collagen Coupled Data Development Disease Drug Kinetics Endothelial Cells Enzymes Equilibrium Etiology Event Extracellular Matrix Failure Fibroblasts Fibrosis Functional disorder Gene Transfer Genetic Genomics Heart failure Hematopoietic Hematopoietic stem cells Homeostasis Homing Human Hydrophobicity Hypertrophy Hypoxia Industrial Waste Infiltration Inflammatory Injury Investigation Kidney Knock-out Knockout Mice Lead Libraries Life Style Literature Lung Mediating Modeling Motion Obesity Outcome Patients Peptidyl-Dipeptidase A Phase Physiological Positioning Attribute Prevalence Prevention Production Property Publishing Pulmonary Fibrosis Pulmonary Heart Disease Pulmonary Hypertension Pulmonary vessels Rattus Renin-Angiotensin System Right Ventricular Function Right Ventricular Hypertrophy Risk Factors Side Signal Transduction Site Smoking Smooth Muscle Stem cells Structure System Testing Therapeutic Toxicology Toxin Transgenic Organisms Translating United States Food and Drug Administration Vascular Endothelial Cell Vascular remodeling Vasocon Vasoconstrictor Agents Vasodilator Agents Ventricular angiotensin I (1-7)arm base bone morphogenetic protein receptors cytokine improved innovation meetings mouse model novel overexpression pressure prevent public health relevance receptor repaired restoration sedentary small molecule success therapeutic gene treatment strategy vascular endothelial dysfunction

项目摘要

DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is a devastating disease of diverse etiology that leads to progressive right heart failure and death. It has been proposed that an imbalance between vasoconstrictive and vasodilator mechanisms initiated by pulmonary endothelial dysfunction causes an increased pulmonary vascular remodeling, and fibrosis leading to right ventricular failure and PH. Based on evidence from the literature and our preliminary data, we propose that a balance between endothelial angiotensin converting enzyme (ACE) and ACE2 is critical in maintaining normal pulmonary vascular homeostasis. Thus, an imbalance in ACE/ACE2 is central in the initiation of pathophysiological events leading to PH. We hypothesize that increasing levels of ACE2 or its enzymatic product, Angiotensin-(1-7) [Ang-(1-7)], in the lungs would reverse endothelial dysfunction, decrease pulmonary vascular remodeling, improve right ventricular function and therefore protect and ameliorate or reverse PH. We propose the following aims to support or refute this hypothesis: Aim 1 will use two additional animal models of PH (hypoxia rat, and bone morphogenetic protein receptor 2, Bmpr2, conditional knockout mouse) to establish the concept that increases in pulmonary ACE2 or Ang-(1-7) would reverse PH. Aim 2 will test the hypothesis that a newly discovered ACE2 activator, DIZE, would reverse PH. In addition, we will investigate the mechanism of DIZE's actions on the pulmonary vessels. Aim 3 will investigate the hypothesis that local delivery of ACE2 or Ang-(1-7) by hematopoietic stem cells expressing these therapeutic genes will reverse PH. This multi-disciplinary and physiological genomic approach to investigate the hypothesis that the endothelial ACE/ACE2 is key to the PH pathophysiology is both novel and innovative. In addition, it will: (i) provide evidence that restoration of ACE/ACE2 imbalance in the pulmonary vasculature would reverse PH, and (ii) put us in an outstanding position to translate our hypothesis driven animal investigations into clinical phase trial for PH. PUBLIC HEALTH RELEVANCE: Endothelial dysfunction is one of the early cellular events in the development of cardiopulmonary diseases. Our objective in this investigation is to test the hypothesis that an imbalance in the activities of the vasoconstrictive, proliferative, fibrotic axis (ACEAngII- AT1R) and vasoprotective axis [ACE2-Ang-(1-7)-Mas receptor] of the reninangiotensin system initiates a cascade of signaling events leading to endothelial dysfunction. Thus, restoring a balance by activation of ACE2 or by genetically modified hematopoietic stem cell to deliver ACE2/Ang-(1-7) would orchestrate a robust pulmonary vascular repair and reverse pulmonary hypertension.

描述（由申请人提供）：肺动脉高压（PH）是一种具有多种病因的破坏性疾病，可导致进行性右心衰竭和死亡。有人提出，肺内皮功能障碍引发的血管收缩和血管舒张机制之间的不平衡会导致肺血管重塑增加和纤维化，导致右心室衰竭和肺动脉高压。根据文献证据和我们的初步数据，我们提出内皮血管紧张素转换酶 (ACE) 和 ACE2 之间的平衡对于维持正常的肺血管稳态至关重要。因此，ACE/ACE2 的不平衡是引发 PH 的病理生理事件的核心。我们假设增加水平肺中的 ACE2 或其酶产物血管紧张素-(1-7) [Ang-(1-7)] 会逆转内皮功能障碍，减少肺血管重塑，改善右心室功能，从而保护和改善或逆转 PH。我们提出以下目标来支持或反驳这一假设：目标 1 将使用另外两种 PH 动物模型（缺氧大鼠、骨形态发生蛋白受体 2、Bmpr2、条件敲除小鼠）来建立肺 ACE2 或 Ang 增加的概念-(1-7) 将反转 PH。目标 2 将检验新发现的 ACE2 激活剂 DIZE 可以逆转 PH 的假设。此外，我们还将研究DIZE对肺血管的作用机制。目标 3 将研究以下假设：表达这些治疗基因的造血干细胞局部递送 ACE2 或 Ang-(1-7) 将逆转 PH。这种多学科和生理基因组方法来研究内皮 ACE/ACE2 是 PH 病理生理学关键的假设，既新颖又具有创新性。此外，它将：(i) 提供证据表明恢复肺血管系统中 ACE/ACE2 失衡将逆转 PH，并且 (ii) 使我们处于有利地位，可以将我们的假设驱动的动物研究转化为 PH 的临床阶段试验。公共卫生相关性：内皮功能障碍是心肺疾病发展的早期细胞事件之一。我们这项调查的目的是检验假设血管收缩、增殖、纤维化轴的活动不平衡（ACEAngII- AT1R) 和肾素血管紧张素系统的血管保护轴 [ACE2-Ang-(1-7)-Mas 受体] 启动一系列信号事件，导致内皮功能障碍。因此，通过激活 ACE2 或通过基因改造造血干细胞传递 ACE2/Ang-(1-7) 来恢复平衡，将协调强有力的肺血管修复并逆转肺动脉高压。