ANGIOTENSIN II, OXIDATIVE STRESS, AND ATHEROSCLEROSIS

描述：(改编自《调查者摘要》)：氧化应激 被认为参与了伴随的血管功能障碍和重塑 血管紧张素II(AII)引起的高血压，但来源和细胞来源 氧化剂种类及其确切作用还知之甚少。最新研究 在两个PI的实验室中，已经阐明了主动脉的一个新角色 外膜是超氧阴离子(O2-)和硝酸根的形成场所 氧(NO)自由基，表明外膜是 氧化应激。新的研究表明，O2-by的精确度增加 血管外膜明显的硝基酪氨酸染色提示AII，很可能 由于产生O2-和NO的反应产物，过氧亚硝酸根 (Oono-)。血管壁中O2-的来源很多，但最近的研究 表明中性粒细胞NAD(P)H氧化酶存在多个亚基 在O2-最强的外膜中。所有人都参与的初步研究 给缺乏一个NADPH氧化酶亚基gp91Phox的小鼠注射， 显示对ALII的钝性主动脉O2-、肥大和增殖反应 与野生型小鼠相比，尽管有相似的高血压反应。建议 对大鼠和小鼠的研究将阐明氧化应激的假设 外膜NAD(P)H氧化酶衍生的O2-参与 AII诱导的肌源性、肥大和增殖性血管反应 高血压。拟议的研究还将利用前期工作。 载脂蛋白E基因缺陷小鼠(EKO)AII诱导的意义 动脉粥样硬化中的氧化应激。对这些小鼠的初步研究表明 卡托普利和氯沙坦可减少动脉粥样硬化(提示对AII有作用)， 假设在所有人的影响下， O2-和Oono-的产生，在初步研究中表明 硝基酪氨酸。高表达人铜/锌超氧化物歧化酶载脂蛋白E缺陷小鼠的研究 以及缺乏载脂蛋白E和gp91Phox或AII型受体的双基因敲除， 将有助于阐明AII诱导氧化应激的假说 对血管功能障碍和血管重塑有显著影响 动脉硬化。

DESCRIPTION: (Adapted from the Investigator's Abstract): Oxidative stress is thought to participate in vascular dysfunction and remodeling that accompanies angiotensin II (AII)-induced hypertension, but the source and cellular sources of oxidant species and their precise role is poorly understood. Recent studies in the laboratories of the two PI's have elucidated a novel role for the aortic adventitia as the site of elaboration of both superoxide anion (O2-) and nitric oxide (NO) radicals, indicating that the adventitia is a major site of oxidative stress. New studies indicate that the increased elaboration of O2- by AII is indicated by prominent nitrotyrosine staining of the adventitia, likely as a result of production of the reaction product of O2- and NO, peroxynitrite (OONO-). There are many sources of O2- in the vascular wall, but recent studies indicate that multiple subunits of the neutrophil NAD(P)H oxidase are present in the adventitia where O2- is greatest. Preliminary studies in which AII was infused into mice that are deficient in one NADPH oxidase subunit, gp91phox, show a blunted aortic O2-, hypertrophic, and proliferative response to AII compared with wild type mice, despite a similar hypertensive response. Proposed studies in rats and mice will elucidate the hypothesis that oxidative stress mediated by adventitial NAD(P)H oxidase-derived O2- participates in the myogenic, hypertrophic, and proliferative vascular response in AII-induced hypertension. The proposed studies will also take advantage of preliminary work on Apo E deficient mice (EKO) to determine the significance of AII-induced oxidative stress in atherosclerosis. Preliminary studies in these mice indicate that captopril and losartan reduce atherosclerosis (suggesting a role for AII), and that hypothetically under the influence of AII, there is increased production of O2- and OONO-, as indicated in preliminary studies by nitrotyrosine. Studies in Apo E deficient mice that overexpress human Cu/Zu SOD and double knockouts deficient in Apo E and gp91 phox or the AII type receptor, will help to elucidate the hypothesis that AII-induced oxidative stress contributes significantly to vascular dysfunction and remodeling in atherosclerosis.