Reactive Oxygen Species in Vascular Disease

血管疾病中的活性氧

基本信息

批准号：
7595170
负责人：
Patrick J Pagano
金额：
$ 37.32万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7595170
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Abbreviations Address Amino Acids Angioplasty Angiotensin II Atherosclerosis Attenuated Balloon Angioplasty Binding Biological Assay Blood Vessels Cardiovascular Diseases Carotid Arteries Catalytic Domain Cells Chimeric Proteins Common carotid artery Data Diabetes Mellitus Disease Docking Dose Effectiveness Endothelial Cells Enzyme-Linked Immunosorbent Assay Enzymes Fatty acid glycerol esters Fibroblasts Generations Growth HIV Homologous Gene Hormones Hydrogen Peroxide Hyperplasia Hypertension Hypertrophy In Vitro Individual Infusion procedures Inhibitory Concentration 50 Injury Knowledge Lead Literature Medial Mediating Membrane Modeling NADH NADP NADPH Oxidase Names Nitric Oxide Oxidants Oxidases Peptides Phagocytes Play Process Production Protein Isoforms Rattus Reactive Oxygen Species Relative (related person)Relaxation Research Personnel Role Signal Transduction Smooth Muscle Myocytes Stretching Superoxide Dismutase Superoxides System Testing Thrombin Tumor Necrosis Factor-alpha Up-Regulation Vascular Diseases Vascular Patency alpha-Thrombin base cofactor comparative efficacy digital diphenyleneiodonium human CYBA protein improved in vitro Model in vitro activity in vivo inhibitor/antagonist morphometry neutrophil cytosol factor 67K novel prevent prototype research study response response to injury stem superoxide-generating NADPH oxidase

项目摘要

DESCRIPTION (provided by applicant): NAD(P)H oxidases are broadly activated in cardiovascular diseases, including hypertension, atherosclerosis, and diabetes. Reactive oxygen species (ROS) derived from these oxidases have been implicated in impaired vascular relaxation, medial hypertrophy, and neointimal hyperplasia in various forms of hypertension. NAD(P)H oxidase-derived superoxide anion (O2-) and other ROS are believed to mediate stretch-induced signaling, leading to neointimal hyperplasia. We previously developed a cell-permeant inhibitor of gp91-phox- (nox2-) based oxidase assembly which is capable of abrogating vascular O2- production in response to angiotensin II. The current proposal stems from 3 major findings, demonstrating (a) the importance of the multi-component oxidase assembly in vascular O2- production; (b) the ability of our cell-permeant inhibitor of nox2-based oxidase assembly to inhibit O2- and attenuate neointimal proliferation of the rat carotid artery in response to balloon angioplasty; and (c) the upregulation of novel nox2 homologues, nox1 and nox4, in response to balloon injury. Since nox1 and nox4 appear to be important oxidase homologues involved differentially in vascular O2- production after stretch, we will determine the efficacy of docking sequence mimics (which inhibit nox1and nox4 assembly with other oxidase subunits) to inhibit whole-vessel and endothelial, smooth muscle cell and fibroblast O2- generation and neointimal proliferation. These studies will address the hypothesis that nox1 and nox4 are functionally involved in vascular stretch-induced oxidase assembly and O2- generation, leading to neointimal proliferation. Three specific aims will be tested: (1) to develop specific inhibitors of nox1- and nox4-based oxidases and test them in an in vitro model of hormone-induced vascular NAD(P)H oxidase activation; (2) to investigate the role of docking sequences on individual nox-based oxidases in vascular stretch-induced oxidase activity in vitro; and (3) to determine the role of nox docking sequences in balloon angioplasty-induced neointimal hyperplasia in vivo. Relevance: Therapies aimed at disrupting the various NAD(P)H oxidase systems in blood vessels should substantially improve vascular patency and function following balloon angioplasty. These inhibitors are also expected to provide broad utility in a variety of disease processes involving oxidants, including hypertension, diabetes and atherosclerosis.

描述（由申请人提供）：NAD(P)H 氧化酶在心血管疾病中广泛激活，包括高血压、动脉粥样硬化和糖尿病。源自这些氧化酶的活性氧（ROS）与各种形式的高血压中的血管舒张受损、内侧肥大和新内膜增生有关。 NAD(P)H 氧化酶衍生的超氧阴离子 (O2-) 和其他 ROS 被认为可介导拉伸诱导的信号传导，导致新内膜增生。我们之前开发了一种基于 gp91-phox- (nox2-) 的氧化酶组件的细胞渗透抑制剂，它能够响应血管紧张素 II 消除血管 O2 的产生。目前的提议源于 3 个主要发现，证明了 (a) 多组分氧化酶组装在血管 O2 产生中的重要性； (b) 我们的基于 nox2 的氧化酶组装体的细胞渗透性抑制剂能够抑制 O2- 并减弱大鼠颈动脉对球囊血管成形术的反应的新内膜增殖； (c) 新型 nox2 同源物、nox1 和 nox4 因球囊损伤而上调。由于 nox1 和 nox4 似乎是重要的氧化酶同源物，在拉伸后差异性地参与血管 O2 产生，因此我们将确定对接序列模拟物（抑制 nox1 和 nox4 与其他氧化酶亚基组装）抑制全血管和内皮、平滑肌的功效细胞和成纤维细胞 O2- 生成和新内膜增殖。这些研究将提出这样的假设：nox1 和 nox4 在功能上参与血管拉伸诱导的氧化酶组装和 O2 生成，从而导致新内膜增殖。将测试三个具体目标：（1）开发基于 nox1 和 nox4 的氧化酶的特异性抑制剂，并在激素诱导的血管 NAD(P)H 氧化酶激活的体外模型中对其进行测试； (2) 研究对接序列对单个基于 nox 的氧化酶在体外血管拉伸诱导的氧化酶活性中的作用； (3)确定nox对接序列在球囊血管成形术诱导的体内新生内膜增生中的作用。相关性：旨在破坏血管中各种 NAD(P)H 氧化酶系统的疗法应能显着改善球囊血管成形术后血管的通畅性和功能。这些抑制剂还有望在涉及氧化剂的各种疾病过程中提供广泛的用途，包括高血压、糖尿病和动脉粥样硬化。