Nox 4 modulation of NO bioavailability and vascular function

Nox 4 调节 NO 生物利用度和血管功能

基本信息

批准号：
8209064
负责人：
SIOBHAN M CRAIGE
金额：
$ 5.57万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2010-01-22 至 2013-01-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8209064
关键词：
Address Arginine Biological Availability Blood Platelets Blood Vessels Blood capillaries Cardiovascular Diseases Cardiovascular system Citrulline Clinical Cyclic GMP Data Endothelial Cells Endothelium Enzymes Event Family Functional disorder Goals Heat-Shock Proteins 90 Hindlimb Homeostasis Human Impairment Inflammation Ischemia Limb structure Mediating Messenger RNA Modeling Molecular Morbidity - disease rate Myocardial Infarction NADPH Oxidase Nitric Oxide Nitric Oxide Synthase Pathologic Patients Phenotype Phosphorylation Phosphotransferases Physiological Production Protein Isoforms Proteins Reactive Oxygen Species Recovery Regulation Relaxation Role Secondary to Source Stroke Vascular Diseases Vascular Endothelium Work adenylate kinase angiogenesis capillary design improved in vivo indexing insight migration mortality mouse model novel overexpression protein tyrosine phosphatase 1B response

项目摘要

DESCRIPTION (provided by applicant): The endothelium is an important component of normal vascular homeostasis, in part, through its production of nitric oxide (NO?) via the endothelial isoform of nitric oxide synthase (eNOS). In patients with cardiovascular disease, impaired endothelial NO? bioactivity leads to a loss of the normal endothelial inhibition of platelet activity and inflammation, predisposing patients to clinical cardiovascular events such as heart attack and stroke. This impairment of endothelial NO? bioactivity is thought secondary to increased vascular levels of reactive oxygen species (ROS) that chemically destroy NO? and promote a maladaptive vascular phenotype. Vascular ROS are produced by a number of enzymes, although the NADPH oxidase (Nox) family appears important for endothelial dysfunction. However, recent data indicate that some Nox isoforms are active in "normal" vasculature and Nox4 is particularly abundant in the endothelium. In this application, data are presented that Nox4 promotes endothelial NO? bioactivity and is important for normal phenotypic responses such as endothelial proliferation and angiogenesis. Thus, the central hypothesis of this proposal is that Nox4 promotes normal endothelial function. To address this hypothesis, the role of Nox4 in modulating eNOS will be characterized and underlying mechanisms probed including Akt, AMP kinase, and protein tyrosine phosphatase 1B. Subsequently, the role of Nox4 on modulating phenotypic endothelial responses important for angiogenesis such as proliferation, migration, and recovery from hindlimb ischemia will be examined. The work contained in this proposal will be important for defining the molecular events that distinguish adaptive ROS-mediated responses from those that are maladaptive and contribute to cardiovascular disease. As a consequence, this work will help provide the necessary insight to design new treatments for cardiovascular disease, the principal source of morbidity and mortality in the developed world.

描述（由申请人提供）：内皮是正常血管稳态的重要组成部分，部分通过其通过一氧化氮合酶（ENOS）的内皮同工型生产一氧化氮（NO？）。在心血管疾病的患者中，内皮疾病没有？生物活性导致血小板活性和炎症正常内皮抑制作用的丧失，使患者易患临床心血管事件，例如心脏病发作和中风。内皮的这种障碍不是吗？生物活性被认为是化学破坏NO的活性氧（ROS）的血管水平升高的继发性？并促进适应不良的血管表型。血管ROS由许多酶产生，尽管NADPH氧化酶（NOX）家族对于内皮功能障碍似乎很重要。但是，最近的数据表明，某些NOX同工型在“正常”脉管系统中活跃，而NOX4在内皮中特别丰富。在此应用程序中，显示了NOX4促进内皮NO的数据吗？生物活性，对于正常的表型反应（例如内皮增殖和血管生成）很重要。因此，该提议的中心假设是NOX4促进了正常的内皮功能。为了解决这一假设，NOX4在调节eNOS中的作用将被表征和潜在的机制，包括AKT，AMP激酶和蛋白质酪氨酸磷酸酶1B。随后，将检查NOX4在调节表型内皮反应中对血管生成重要的作用，例如增殖，迁移和从后肢缺血中恢复。本提案中包含的工作对于定义分子事件将适应性ROS介导的反应与适应不良的反应并导致心血管疾病的反应很重要。结果，这项工作将有助于提供必要的见解，以设计针对心血管疾病的新疗法，这是发达国家发病率和死亡率的主要来源。