Hypertension and Superoxide Generation

高血压和超氧化物的产生

• 批准号: 6438238
• 负责人: Patrick J Pagano
• 金额: $ 21.45万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6438238
• 关键词: NAD(P)H dehydrogenase; angiotensin II; cardiovascular injury; cell migration; cell proliferation; enzyme activity; enzyme mechanism; genetically modified animals; glutathione peroxidase; green fluorescent proteins; hypertension; laboratory mouse; oxidative stress; oxidoreductase inhibitor; superoxide dismutase; superoxides; tissue /cell culture; vascular smooth muscle; vasomotion

DESCRIPTION (provided by the applicant): In this proposal, we will investigate the role of adventitia-derived superoxide O2 in vascular reactivity, hypertrophy and injury response in hypertension. The proposal stems from our previous findings (a) documenting expression of phagocyte-like NADPH oxidase components in the adventitia of arteries: (b) demonstrating that this enzyme is the major source of vascular O2 (C) demonstrating that p67Ph0x. a critical component in phagocyte NADPH oxidase activity is essential to vascular oxidase activity: (d) showing that AngII-induced elevation of vascular O2 is associated with transcriptional activation of adventitial NADPH oxidase: and (e) demonstrating that now el inhibitors of this enzyme attenuate AngII-induced O2 production. While our data have established the presence of a vascular NADPH oxidase source of O2 and revealed some of its molecular character. little is known of its regulation, or the significance of its location in the adventitia. We will address tine physiological significance of NADPH oxidase by testing tine hypothesis that increased vascular levels of O2 via adventitial NADPH oxidase expression and assembly of its components during the development of AngII-dependent hypertension impair endothelium-dependent responses. and enhance the medial in hypertrophic response and neointimal proliferative response to injury, in testing this hypothesis. we will (1) examine a variety of cell-permeant chimeric peptide sequences that we developed as to their effectiveness in blocking assembly of the oxidase, vascular O2 generation, and attenuating AngII-dependent blood pressure elevation: (2) target these NADPH oxidase inhibitors to various vascular cell types by adenoviral transfection and development of a transgenic mouse model and examine tine effect on endothelium-dependent responses: (3) examine the effect of cell targeting on medial hypertrophy. and compare responses in glutathione peroxidase-l-deficient versus wild-type mice (4) examine the effect of cell targeting on mvofibroblast migration and neointimal proliferation during the vascular injury response.

描述（由申请人提供）：在本提案中，我们将调查 血管外膜来源的超氧O2在血管反应性中的作用， 高血压时心肌肥厚和损伤反应。该提案源于我们的 先前的发现（a）记录吞噬细胞样NADPH氧化酶的表达 （B）证明这种酶是 血管O2的主要来源（C）表明p67 Ph 0x.一个关键 吞噬细胞中的NADPH氧化酶活性组分是血管氧化酶所必需的 活性：（d）显示AngII诱导的血管O2升高与 具有外膜NADPH氧化酶的转录激活;和（e） 这表明该酶的E1抑制剂减弱AngII诱导的O2 生产虽然我们的数据已经确定了血管NADPH的存在， O2氧化酶的来源，并揭示了它的一些分子特征。之甚少 已知其调节或其在外膜中的位置的重要性。 我们将通过测试来说明NADPH氧化酶的生理意义。 通过外膜NADPH增加血管O2水平的假说 氧化酶的表达和组装，其组件在发展过程中， AngII依赖性高血压损害内皮依赖性反应。和 增强中膜肥厚反应和新生内膜增生 对损伤的反应，来检验这个假设。我们将（1）检查各种 我们开发的细胞渗透嵌合肽序列， 有效阻止氧化酶组装、血管O2生成， 减弱AngII依赖性血压升高：（2）靶向这些NADPH 通过腺病毒转染对各种血管细胞类型的氧化酶抑制剂 转基因小鼠模型的建立， 内皮依赖性反应：（3）检查细胞靶向对内皮依赖性反应的影响。 中膜肥大并比较谷胱甘肽过氧化物酶-l缺乏 与野生型小鼠相比（4）检查细胞靶向对mvo成纤维细胞的影响 血管损伤反应期间的迁移和新生内膜增殖。