VASCULAR NAH/NADPH OXIDASE

血管NAH/NADPH氧化酶

• 批准号: 6574789
• 负责人: Kathy K Griendling
• 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/6574789
• 关键词: NAD(P)H dehydrogenase; angiotensin II; arachidonate; catalase; eicosanoid metabolism; enzyme activity; enzyme mechanism; hormone receptor; hydrogen peroxide; muscle hypertrophy; nucleic acid probes; oxidative stress; superoxides; transfection; vascular smooth muscle

The mechanisms responsible for the vascular growth and hypertrophy that accompanies hypertension are unclear. Our recent observations suggest that reactive oxygen species may serve as a hypertrophic signal in cultured vascular smooth muscle cells. In many other systems, most notably tumor cells, oxygen-derived free radicals stimulate growth, implying that the redox state of the cell may be a common step at which growth control can be achieved. Therefore, the proteins and enzymes that produce reactive oxygen species or serve as the antioxidant defense system are critical determinants of the course of vascular disease. In cultured vascular smooth muscle cells, we have shown that vasoactive agents such as angiotensin II cause a delayed generation of superoxide anion by activating a NADH/NADPH oxidase located in the cell membrane. The pathways leading to oxidase activation and the pathways linking oxidase activation to hypertrophy will be examined in this project. In the first specific aim, we will determine the role of arachidonic acid metabolites and tyrosine kinases in activation of the NADH/NADPH oxidase. In Specific Aim 2, we plan to use p22phox, a key component of the vascular oxidase, to identify other subunits, and to began to examine regulation of oxidase expression. Since the superoxide that is produced by this enzyme system is rapidly dismuted to H202, it is unclear which reactive oxygen species mediate the hypertrophic response to angiotensin II. This question will be addressed in Specific Aim 3, using cells over- and under-expressing catalase. Finally, in Specific Aim 4, we will determine the role of the NADH/NADPH oxidase system in hypertrophy in vivo, using rats made hypertensive by angiotensin II infusion and transgenic mice that over- or under-express p22phox (made by Dr. Harrison in Project 2). These studies will provide insight into the mechanisms responsible for vascular hypertrophy in hypertension. We hypothesize that modification of NADH/NADPH oxidase activity and therefore the oxidative state of the smooth muscle cells may be central to controlling the expression of a subset of genes involved in the development of hypertension. Understanding the cellular events involved in controlling the oxidative environment of VSMC may thus lead to a more in depth understanding of vascular disease processes and the development of specific therapeutic strategies.

导致血管生长和肥大的机制 伴发高血压的原因尚不清楚。我们最近的观察表明 活性氧可作为培养细胞肥大的信号 血管平滑肌细胞。在许多其他系统中，最著名的是肿瘤 细胞，氧衍生的自由基刺激生长，这意味着 细胞的氧化还原状态可以是生长控制可以 才能实现。因此，产生反应性的蛋白质和酶 氧物种或作为抗氧化防御系统是至关重要的 血管疾病病程的决定因素。在培养的血管中 我们已经证明了血管活性物质，如 血管紧张素II通过以下方式延迟超氧阴离子的产生 激活位于细胞膜上的NADH/NADPH氧化酶。小路 导致酶的激活和连接酶激活的途径 到肥大将在这个项目中被研究。在第一个具体的 目的，我们将确定花生四烯酸代谢物和 酪氨酸激酶在NADH/NADPH氧化酶激活中的作用以特定的目标 2，我们计划使用血管氧化酶的关键成分p22Phox来 鉴定其他亚基，并开始研究氧化酶的调节 表情。因为这个酶系统产生的超氧化物是 迅速变异为H202，目前尚不清楚哪些活性氧物种 调节血管紧张素II的肥大反应。这个问题将是 在具体目标3中解决，使用过度表达和低表达的细胞 过氧化氢酶。最后，在具体目标4中，我们将确定 NADH/NADPH氧化酶系统在大鼠体内肥大中的作用 血管紧张素II输注引起的高血压和过量表达的转基因小鼠 表达不足的p22Phox(由哈里森博士在项目2中制作)。这些研究 将提供对血管形成的机制的洞察 高血压时的肥大。我们假设，对 NADH/NADPH氧化酶活性及其氧化状态 平滑肌细胞可能是控制一种蛋白表达的中心 参与高血压发展的基因的子集。理解 参与控制氧化环境的细胞事件 因此，VSMC可能会导致对血管疾病的更深入了解 过程和特定治疗策略的发展。