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）已与各种形式的高血压中的血管松弛，内侧肥大和新内膜增生有关。 NAD（P）H氧化酶衍生的超氧化阴离子（O2-）和其他ROS被认为介导拉伸诱导的信号传导，导致新的增生。我们以前开发了一种基于GP91-磷酸（NOX2-）的氧化酶组装的细胞 - 烧烤抑制剂，该酶的氧化酶组装能够响应血管紧张素II，可以废除血管O2-产生。当前的提案源于3个主要发现，证明了（a）多组分氧化酶组装在血管O2生产中的重要性；（b）基于NOX2的氧化酶组装的细胞 - 烧烤抑制剂抑制O2-并减轻大鼠颈动脉的新内膜增殖，以响应球囊血管成形术；（c）新型NOX2同源物NOX1和NOX4的上调，以响应气球损伤。由于NOX1和NOX4似乎是重要的氧化酶同源物在伸展后的血管O2产生中差异涉及，因此我们将确定对接序列模拟物的功效（抑制NOX1和NOX4与其他氧化酶亚基的组装）以抑制全氧化和内皮，平滑的肌肉和光滑的肌肉和Fibroblo o2-neoint and N.Imim o2 o2 o2 o2 o2 o2 o2 o2 and and and plult。这些研究将解决以下假设：NOX1和NOX4在功能上与血管拉伸诱导的氧化酶组装和O2生成有关，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的氧化酶的特定抑制剂，并在激素诱导的血管NAD（P）H氧化酶激活的体外模型中测试它们；（2）研究对接序列对基于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对接序列在气囊血管成形术引起的体内新内膜增生中的作用。相关性：旨在破坏血管中各种NAD（P）H氧化酶系统的疗法应大大改善气球血管成形术后血管通畅和功能。这些抑制剂还有望在涉及氧化剂（包括高血压，糖尿病和动脉粥样硬化）的各种疾病过程中提供广泛的效用。