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: 6389540
• 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/6389540
• 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