Hypertension and Superoxide Generation

高血压和超氧化物的产生

• 批准号: 6832251
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832251
• 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 外膜衍生的超氧阴离子在血管反应性中的作用， 高血压患者的肥大和损伤反应。这项建议源于我们的 以前的发现(A)记录了吞噬细胞样NADPH氧化酶的表达 动脉外膜成分：(B)证明该酶是 血管O2(C)的主要来源表明p67Ph0x。一位批评者 吞噬细胞中的NADPH氧化酶活性对血管氧化酶是必不可少的 活性：(D)表明血管紧张素转换酶诱导的血管氧含量升高与 外膜NADPH氧化酶转录激活：和(E) 证明现在这种酶的EL抑制剂可以减弱血管紧张素转换酶诱导的氧 制作。虽然我们的数据已经证实了血管性NADPH的存在 O2的来源，揭示了它的一些分子特征。小才是 已知其规则，或其在外膜中的位置的重要性。 我们将通过测试来阐述NADPH氧化酶的生理意义 外膜NADPH增加血管氧气水平的两个假说 细胞发育过程中氧化酶的表达及其组成成分的组装 血管紧张性高血压损害血管内皮依赖性反应。和 增强中膜的肥大反应和新生内膜的增殖 在检验这一假说时，对伤害的反应。我们将(1)研究各种 我们开发的细胞嵌合多肽序列 有效地阻止了氧化酶的组装，血管中O2的产生，以及 减轻血管紧张素转换酶依赖性血压升高：(2)针对这些NADPH 腺病毒转染法对不同类型血管细胞的氧化酶抑制作用 建立转基因小鼠模型并检测其对小鼠生长发育的影响。 内皮依赖性反应：(3)检测细胞靶向对血管内皮细胞的影响 内侧肥大。并比较谷胱甘肽过氧化物酶-L缺陷型的反应 与野生型小鼠比较(4)细胞靶向对成纤维细胞的影响 血管损伤反应中的迁移和新生内膜增殖。

项目成果

Thrombospondin-1 regulates blood flow via CD47 receptor-mediated activation of NADPH oxidase 1.

血小板传播1通过CD47受体介导的NADPH氧化酶1的激活调节血液流动。

• DOI: 10.1161/atvbaha.112.300031
• 发表时间: 2012-12
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Csányi G;Yao M;Rodríguez AI;Al Ghouleh I;Sharifi-Sanjani M;Frazziano G;Huang X;Kelley EE;Isenberg JS;Pagano PJ
• 通讯作者: Pagano PJ