PHENOTYPIC CONSEQUENCES OF VASCULAR OXIDANT STRESS

血管氧化应激的表型后果

• 批准号: 6574790
• 负责人: David G Harrison
• 金额: $ 17.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6574790
• 关键词: NAD(P)H dehydrogenase; enzyme activity; free radical oxygen; free radical scavengers; genetically modified animals; hypertension; laboratory mouse; metalloendopeptidases; nitric oxide; oxidative stress; vascular smooth muscle

During the past several years, it has become apparent that both endothelial and vascular smooth muscle cells produce superoxide (.O2-) and other reactive oxygen species. Research from our laboratory has shown that in certain disease processes, production of .02- decrease the biological effects of endothelium-derived nitric oxide (NO.). The enzyme systems involved in this process remain incompletely defined and the consequences of alterations of rates of production of reactive oxygen species in the vessel wall are not fully understood. The research planned will examine several aspects of vascular oxygen radical production. Recent work by Dr. Griendling, the director of project 1 in this program project grant, has suggested that p22phox plays an important role in function of a membrane- bound NADH/NADPH-dependent oxidase. In collaboration with Dr. Griendling, we have shown that expression of this portion of the oxidase is increased in the setting of angiotensin II-induced hypertension. Studies are designed to examine the effect of both over expression and inhibition of expression of p22phox on vascular reactivity and blood pressure in transgenic mice. We have recently shown that a significant proportion of angiotensin II-induced hypertension is due to an increase in vascular .02- production. Studies will be performed to determine if this effect is dependent on 02-interacting with NO., or if this phenomena can occur in mice lacking endothelial cell NO synthase. A final aim will be devoted to understanding a new role of oxygen-derived radicals in activation of matrix metalloproteinases (MMPS). Preliminary data show that reactive oxygen species can directly activate MMP-2 and -9. We plan experiments t further understand the phenomenon and to determine if other, biologically relevant reactive oxygen species can activate MMPs. We will also determine if chronic elevation of circulating angiotensin II, a condition associated with increase in vascular .02 production, is also associated with activation of MMPs in vivo. These studies will involve transgenic and "knockout" mice with specific genetic alterations relative to vascular 02- and NO2. production, and promise to provide new and important information regarding interactions between these important radicals.

在过去的几年里，很明显，两者都 血管内皮细胞和血管平滑肌细胞产生超氧化物(.O2-)和 其他活性氧物种。我们实验室的研究表明 在某些疾病过程中，0.02-的产生减少了生物 内皮源性一氧化氮(NO)的作用。酶系统 参与这一进程的定义仍然不完全，其后果是 活性氧物种产生速率的变化 对脉管壁的认识还不够深入。计划中的研究将检查 血管氧自由基产生的几个方面。最近的研究工作由Dr。 格里恩德林是该计划项目赠款中项目1的负责人，他已经 提示p22Phox在膜的功能中起重要作用- 结合NADH/NADPH依赖的氧化酶。在与格里德林博士的合作下， 我们已经证明，这部分氧化酶的表达增加了 在血管紧张素II诱导的高血压的背景下。研究是 被设计用来检查过度表达和抑制 P22Phox在大鼠血管反应性和血压中的表达 转基因小鼠。我们最近表明，相当大比例的 血管紧张素II诱导的高血压是由于血管增加。02- 制作。将进行研究以确定这种影响是否 依赖02-与编号交互，或此现象是否会发生在 内皮细胞缺失的小鼠无合酶。最终目标将致力于 认识氧自由基在细胞活化中的新作用 基质金属蛋白酶(MMPs)。初步数据显示，反应性 氧物种可直接激活基质金属蛋白酶-2和-9。我们计划做实验 进一步了解这一现象并确定是否有其他生物 相关的活性氧物种可以激活MMPs。我们还将确定 如果循环血管紧张素II慢性升高，与 随着血管0.02产量的增加，也与 体内MMPs的激活。这些研究将涉及转基因和 具有与血管02相关的特定基因改变的“基因敲除”小鼠- 和NO2。生产，并承诺提供新的重要信息 关于这些重要的自由基之间的相互作用。