ANGIOTENSIN II, OXIDATIVE STRESS, AND ATHEROSCLEROSIS

血管紧张素 II、氧化应激和动脉粥样硬化

• 批准号: 6793592
• 负责人: RICHARD A COHEN
• 金额: $ 31.5万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6793592
• 关键词: NAD(P)H dehydrogenase; angiogenesis; angiotensin /renin /aldosterone hypertension; angiotensin II; angiotensin receptor; antihypertensive agents; apolipoprotein E; atherosclerosis; blood vessels; cell growth regulation; cell proliferation; enzyme activity; fibroblasts; free radical oxygen; genetically modified animals; immunocytochemistry; laboratory mouse; nitric oxide; oxidative stress; peroxynitrites; superoxides; tissue /cell culture

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.

描述：（改编自研究者摘要）：氧化应激是 被认为参与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 氧化剂种类和它们的确切作用知之甚少。最近的研究 在两个PI的实验室中，已经阐明了主动脉的新作用， 外膜作为超氧阴离子（O2-）和一氧化氮（NO）的产生部位 氧化物（NO）自由基，表明外膜是一个主要的网站， 氧化应激新的研究表明，增加的阐述O2- AII由外膜的明显硝基酪氨酸染色指示，可能 由于O2-和NO的反应产物的产生，过氧亚硝酸盐 （OONO-）.血管壁中的O2-有许多来源，但最近的研究表明， 表明存在嗜中性粒细胞NAD（P）H氧化酶多个亚单位 在O2-最大的外膜中。初步研究中， 输注到一种NADPH氧化酶亚基gp 91 phox缺陷的小鼠中， 显示对AII的主动脉O2-反应迟钝、肥大和增殖 与野生型小鼠相比，尽管有类似的高血压反应。提出 在大鼠和小鼠中的研究将阐明氧化应激 由外膜NAD（P）H氧化酶介导的O2-参与了 AII诱导的肌源性、肥大性和增殖性血管反应 高血压拟议的研究还将利用初步工作 在载脂蛋白E缺陷小鼠（EKO）上，以确定AII诱导的 动脉粥样硬化中的氧化应激对这些小鼠的初步研究表明， 开搏通和氯沙坦可减少动脉粥样硬化（提示AII的作用）， 假设在AII的影响下， O2-和OONO-的产生，如初步研究所示， 硝基酪氨酸过表达人Cu/Zu SOD的Apo E缺陷小鼠的研究 以及Apo E和gp 91 phox或AII型受体缺陷的双敲除， 将有助于阐明AII诱导的氧化应激的假说， 显著促进血管功能障碍和重塑， 动脉粥样硬化

项目成果

Role of superoxide anion in regulating pressor and vascular hypertrophic response to angiotensin II.

• DOI: 10.1152/ajpheart.00914.2001
• 发表时间: 2002-05
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Hui Di Wang;D. Johns;Shanqin Xu;R. Cohen

Adventitia as a source of inducible nitric oxide synthase in the rat aorta.

• DOI: 10.1016/s0895-7061(98)00271-4
• 发表时间: 1999-05
• 期刊: American journal of hypertension
• 影响因子: 3.2
• 作者: Hui Zhang;Yue Du;Richard A. Cohen;A. Chobanian;P. Brecher

Detection of sequence-specific tyrosine nitration of manganese SOD and SERCA in cardiovascular disease and aging.

检测心血管疾病和衰老中锰 SOD 和 SERCA 的序列特异性酪氨酸硝化。

• DOI: 10.1152/ajpheart.01293.2005
• 发表时间: 2006
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Xu,Shanqin;Ying,Jia;Jiang,Bingbing;Guo,Wei;Adachi,Takeshi;Sharov,Viktor;Lazar,Harold;Menzoian,James;Knyushko,TatyanaV;Bigelow,Diana;Schöneich,Christian;Cohen,RichardA
• 通讯作者: Cohen,RichardA

Resistance of endothelium-dependent relaxation to elevation of O(-)(2) levels in rabbit carotid artery.

兔颈动脉内皮依赖性舒张对 O(-)(2) 水平升高的抵抗。

• DOI: 10.1152/ajpheart.1999.277.5.h2109
• 发表时间: 1999
• 期刊: The American journal of physiology
• 作者: Pagano,PJ;Griswold,MC;Najibi,S;Marklund,SL;Cohen,RA
• 通讯作者: Cohen,RA