Reactive Oxygen Species in Vascular Disease

血管疾病中的活性氧

• 批准号: 7791414
• 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
• 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/7791414
• 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

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活化，包括高血压、动脉粥样硬化和糖尿病。这些氧化酶衍生的活性氧（ROS）与各种形式的高血压中血管舒张受损、中膜肥大和新生内膜增生有关。NAD（P）H氧化酶衍生的超氧阴离子（O2-）和其他ROS被认为介导牵张诱导的信号传导，导致新生内膜增生。我们以前开发了一种细胞渗透性抑制剂的gp 91-phox-（nox 2-）为基础的氧化酶组装，这是能够废除血管的O2-生产响应血管紧张素II。目前的建议源于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nox 2的氧化酶组装的细胞渗透性抑制剂抑制O2-并减弱大鼠颈动脉对球囊血管成形术的反应的新生内膜增殖的能力;和（c）响应球囊损伤的新NOX 2同系物NOX 1和NOX 4的上调。由于nox 1和nox 4似乎是重要的氧化酶同系物参与差异血管O2-生产后拉伸，我们将确定对接序列模拟物（抑制nox 1和nox 4组装与其他氧化酶亚基）抑制全血管和内皮，平滑肌细胞和成纤维细胞O2-生成和新生内膜增殖的疗效。这些研究将阐明nox 1和nox 4在功能上参与血管牵张诱导的氧化酶组装和O2生成，导致新生内膜增殖的假设。将测试三个具体目标：（1）开发基于nox 1和nox 4的氧化酶的特异性抑制剂，并在血管牵张诱导的血管NAD（P）H氧化酶活化的体外模型中测试它们;（2）研究单个基于nox的氧化酶的对接序列在体外血管牵张诱导的氧化酶活性中的作用;和（3）确定NOx对接序列在体内球囊血管成形术诱导的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氧化酶系统的治疗应能显著改善球囊血管成形术后的血管通畅性和功能。这些抑制剂也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。