Production of vascular superoxide in atherosclerosis

动脉粥样硬化中血管超氧化物的产生

• 批准号: 6480004
• 负责人: DONALD D HEISTAD
• 金额: $ 35.43万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6480004
• 关键词: Macaca fascicularis; NAD(P)H dehydrogenase; angiotensin II; apolipoprotein E; atherosclerosis; cardiovascular function; dietary lipid; free radical oxygen; genetically modified animals; laboratory mouse; low density lipoprotein receptor; nitric oxide synthase; nutrition related tag; oxidative stress; pathogenic diet; platelet derived growth factor; superoxide dismutase; superoxides; tissue /cell culture; vascular endothelium; vascular smooth muscle; vasomotion; xanthine oxidase

Production of reactive oxygen species by blood vessels may contribute to the pathophysiology of atherosclerosis through a variety of mechanisms. Previous studies have focused on the role of reactive oxygen species generated by the endothelium in modulation of vascular function. The investigators have recently shown that superoxide (O2.) levels are increased in vascular smooth muscle cells (SMC) of atherosclerotic compared to normal vessels. The enzymatic sources of SMC O2. in atherosclerosis and its contribution to vascular pathophysiology are not known. The major hypothesis of this project is that generation of O2 by SMC contributes to vascular dysfunction in atherosclerosis. Studies are proposed to examine vessels of a genetic model (ApoE/LDLr deficient mice) and a primate model (cynomolgus monkeys) of atherosclerosis. First, using intact vessels and cultured cells, studies are planned to determine the enzymatic source of O2. in SMC by examining the role of xanthine oxidase, nitric oxide synthase, and NAD(P)H oxidase. Second, studies are planned to determine the potential physiologic importance of SMC O2. and whether levels of O2 can be altered by substances present in the atherosclerotic lesion. The physiologic importance of O2 in SMC from atherosclerotic vessels will be examined by measuring cyclic-GMP in SMC in response to nitric oxide. Studies will determine whether gene transfer of superoxide dismutase to SMC from atherosclerotic vessels improves responsiveness to nitric oxide. In addition, we will examine the role of SMC O2. in atherosclerosis by developing a transgenic model over-expressing superoxide dismutase under the transcriptional control of an SMC-specific SM22alpha promoter. Studies are planned to examine the effects of selective reduction of SMC O2. on the development of vasomoter dysfunction, lesion development, and vascular O2. Studies are proposed to determine whether platelet derived growth factor and angiotensin-II, factors that may be increased in atherosclerosis, augment SMC production of O2. Third, studies are proposed to test the hypothesis that improved vasomoter function during repression of atherosclerosis is associated with reduction in SMC production of O2. Changes in O2. levels will be measured in monkeys after regression of atherosclerosis. The proposed studies are an extension of the novel observation made by the investigators of SMC generation of O2. in atherosclerosis, and may provide findings that alter the view of the role of SMC in atherosclerosis.

血管产生活性氧可能通过多种机制参与动脉粥样硬化的病理生理过程。以往的研究主要集中在内皮细胞产生的活性氧在调节血管功能中的作用。研究人员最近发现，超氧化物（O2。与正常血管相比，动脉粥样硬化的血管平滑肌细胞（SMC）中的水平增加。SMC O2的酶源。在动脉粥样硬化中的作用及其对血管病理生理学的作用尚不清楚。该项目的主要假设是SMC产生O2有助于动脉粥样硬化中的血管功能障碍。提出研究以检查动脉粥样硬化的遗传模型（ApoE/LDLr缺陷小鼠）和灵长类动物模型（食蟹猴）的血管。首先，使用完整的血管和培养的细胞，研究计划确定O2的酶源。通过检测黄嘌呤氧化酶、一氧化氮合酶和NAD（P）H氧化酶在SMC中的作用。其次，计划进行研究以确定SMC O2的潜在生理重要性。以及动脉粥样硬化病变中存在的物质是否可以改变O2水平。动脉粥样硬化血管SMC中O2的生理重要性将通过测量SMC中对一氧化氮的响应的环GMP来检查。研究将确定是否超氧化物歧化酶基因转移到SMC从动脉粥样硬化血管改善一氧化氮的反应性。此外，我们将研究SMC O2的作用。在动脉粥样硬化中，通过开发在SMC特异性SM 22 α启动子的转录控制下过表达超氧化物歧化酶的转基因模型。计划进行研究，以检查选择性减少SMC O2的影响。对血管运动功能障碍、病变发展和血管血氧的影响。研究提出，以确定是否血小板衍生的生长因子和血管紧张素-II，可能会增加动脉粥样硬化的因素，增加SMC生产的O2。第三，研究提出了测试的假设，即改善血管收缩功能的抑制动脉粥样硬化与减少SMC生产的O2。O2的变化。将在动脉粥样硬化消退后在猴中测量水平。拟议的研究是研究人员对SMC产生O2的新观察的延伸。在动脉粥样硬化中的作用，并可能提供改变SMC在动脉粥样硬化中的作用的观点的发现。