Production of vascular superoxide 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。以往的研究主要集中在内皮细胞产生的活性氧在血管功能调节中的作用。研究人员最近发现，与正常血管相比，动脉粥样硬化血管平滑肌细胞（SMC）中的超氧化物（O2）水平升高。SMC O2的酶促来源。动脉粥样硬化及其对血管病理生理的贡献尚不清楚。本项目的主要假设是：动脉粥样硬化中SMC生成O2导致血管功能障碍。研究建议检查动脉粥样硬化的遗传模型（ApoE/LDLr缺陷小鼠）和灵长类模型（食蟹猴）的血管。首先，利用完整的血管和培养的细胞，研究计划确定O2的酶源。通过研究黄嘌呤氧化酶、一氧化氮合酶和NAD(P)H氧化酶在SMC中的作用。其次，研究计划确定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会改变氧水平。我们将通过测量SMC对一氧化氮的反应来检测来自动脉粥样硬化血管的SMC中O2的生理重要性。研究将确定超氧化物歧化酶基因从动脉粥样硬化血管转移到SMC是否能改善对一氧化氮的反应。此外，我们将研究SMC O2的作用。通过在smc特异性SM22alpha启动子的转录控制下，建立过表达超氧化物歧化酶的转基因模型，从而促进动脉粥样硬化的发展。研究计划检验选择性还原SMC O2的影响。血管舒缩功能障碍的发展，病变发展和血管O2。研究建议确定血小板衍生生长因子和血管紧张素- ii，这些可能在动脉粥样硬化中增加的因子，是否增加SMC产生O2。第三，研究人员提出了一种假设，即在动脉粥样硬化抑制过程中血管舒缩功能的改善与SMC生成O2的减少有关。氧的变化。在动脉粥样硬化消退后，将在猴子体内测量其水平。提出的研究是对研究人员对SMC生成O2的新观察的延伸。并可能提供改变SMC在动脉粥样硬化中的作用的发现。

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.