PHENOTYPIC CONSEQUENCES OF VASCULAR OXIDANT STRESS

在过去的几年里，很明显， 内皮细胞和血管平滑肌细胞产生超氧化物（. O2-）， 其他活性氧物质。我们实验室的研究表明， 在某些疾病过程中，.02-减少生物 内皮源性一氧化氮（NO.）的作用。酶系统 参与这一进程的人仍然没有完全确定，其后果 的变化率的生产活性氧物种在 血管壁还不完全清楚。计划中的研究将检查 血管氧自由基产生的几个方面。最近的工作博士。 格里恩德林，在这个项目的项目赠款1主任， 表明p22 phox在膜功能中起重要作用- 结合的NADH/NADPH依赖性氧化酶。与Griendling博士合作， 我们已经表明，这部分氧化酶的表达增加， 血管紧张素II诱导的高血压。研究是 旨在检查过度表达和抑制的影响， p22 phox表达对血管反应性和血压的影响 转基因小鼠我们最近发现， 血管紧张素II引起的高血压是由于血管紧张素II增加。 生产将进行研究，以确定这种影响是否 依赖于O2-与NO的相互作用，或者这种现象是否会发生在 缺乏内皮细胞NO合酶的小鼠。最终目标将致力于 理解氧衍生自由基在活化 基质金属蛋白酶（MMPS）。初步数据显示， 氧物种可直接激活MMP-2和MMP-9。我们计划进行实验， 进一步了解这一现象，并确定是否有其他生物学 相关的活性氧能激活MMPs。我们还将确定 如果循环血管紧张素II的慢性升高， 随着血管.02产生的增加，也与 MMPs在体内的活化。这些研究将涉及转基因和 具有相对于血管02- 04的特定遗传改变的“敲除”小鼠， NO2。生产，并承诺提供新的和重要的信息 关于这些重要的自由基之间的相互作用。

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.