Oxidants and Nitric Oxide in Coronary Vascular Function

氧化剂和一氧化氮对冠状血管功能的影响

• 批准号: 7697583
• 负责人: Michael S Wolin
• 金额: $ 36.41万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7697583
• 关键词: Acute; Aging; Angiotensin II; Animal Model; Animals; Antioxidants; Aorta; Arteries; Behavior; Binding; Blood Pressure; Blood Vessels; Bos taurus; Canis familiaris; Cattle; Chronic; Collaborations; Coronary; Coronary artery; Data; Detection; Disease; Disease model; Endothelium; Energy Metabolism; G6PD gene; Gene Expression; Generations; Genes; Glucosephosphate Dehydrogenase; Glutathione; Link; Mediating; Mediator of activation protein; Membrane Potentials; Metabolic; Mitochondria; Modeling; Mus; Muscle function; NAD(P)H oxidase; NADH; NADP; Nitric Oxide; Nitric Oxide Donors; Organ Culture Techniques; Oxidants; Oxidases; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Pharmaceutical Preparations; Process; Production; Property; Protein Kinase C; Regulation; Regulatory Pathway; Research Personnel; Role; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Sodium-Restricted Diet; Stimulus; Stretching; Study models; Superoxides; System; Tissues; Vascular Diseases; Vascular Smooth Muscle; Work; aged; citrate carrier; db/db mouse; design; diabetic; fluorescence imaging; in vivo; inorganic phosphate; mitochondrial membrane; pressure; programs; research study

The central hypothesis of this project is that specific mechanisms regulating changes in NAD(P)H oxidase (Nox) activity and subunit expression have important roles, in controlling aspects of mediator release from endothelium and signaling mechanisms observed to control vascular smooth muscle contractile function through both changes in ROS and redox control mechanisms. Studies in Aim 1 will define the influence of pathways of Nox oxidase regulation by interactions between Ang II, stretch, a stimuli of protein kinase C (PKC), and altered availability of NAD(P)H on ROS and redox regulation of vascular contractile function in the absence of vascular disease or endothelial factors. The focus of the systems studied include the control of cytosolic NAD(P)H redox and glutathione redox, mitochondria! function (associated with energy metabolism, oxidant production and redox control), and the impact of these systems on specific ROS and redox-controlled signaling mechanisms known to regulate vascular force generation. Studies in Aim 2 examine how changes in Nox activity control endothelial release of NO, ROS and reactive NO-derived species (RNS), and the influence of endothelium and NO-donor drug derived RNS on the systems studied in Aim 1. Emphasis will be placed on building on our previous signaling studies in bovine coronary arteries and extending these studies into mouse aortas due to the availability of mice deficient in the p47phox and Nox-2 (gp91phox) subunits of Nox oxidases. Freshly isolated vascular smooth muscle cells will be studied by fluorescence imaging in the absence and presence of NO-donors to examine relationships between alterations in Nox activation with the detection of changes in ROS and cytosolic and mitochondria! NAD(P)H redox, and indicators of mitochondrial membrane potential and intra-mitochondrial superoxide. A focus of these studies is to develop an understanding processes that control interactions between cytosolic and mitochondrial NAD(P)H redox and ROS generation that are related to the control of vascular force generation. The studies in Aim 3 examine how many of the mechanisms studied in Aim 1 and Aim 2 are altered in vascular tissue derived from animals studied in the other projects exposed to acute and chronic increases in angiotensin II without increased blood pressure, in vivo to alterations in pressure, diabetics and aging.

该项目的中心假设是调节NAD（P）H氧化酶变化的特定机制 （NOX）活动和亚基表达具有重要的作用，在控制介质释放方面 观察到控制血管平滑肌收缩功能的内皮和信号传导机制 通过ROS和氧化还原控制机制的变化。 AIM 1的研究将定义 NOx氧化酶调节ANG II，拉伸，蛋白激酶C刺激的途径 （PKC），并改变了NAD（p）H在ROS和血管收缩功能的氧化还原调节中的可用性 缺乏血管疾病或内皮因素。研究系统的重点包括控制 胞质NAD（P）H氧化还原和谷胱甘肽氧化还原，线粒体！功能（与能量相关联 代谢，氧化剂的产生和氧化还原控制），以及这些系统对特定ROS的影响 氧化还原控制的信号传导机制已知可调节血管力的产生。 AIM 2的研究 检查NOX活动控制NO，ROS和反应性NO的内皮释放的变化如何 物种（RNS），以及内皮和无偏药的RNS的影响对研究的系统 目标1。将重点放在我们先前在牛冠状动脉和 由于p47phox和NOX-2缺乏小鼠的可用性，将这些研究扩展到小鼠主动脉 （gp91phox）Nox氧化酶的亚基。新鲜分离的血管平滑肌细胞将通过 在不存在和存在无偏见的情况下进行荧光成像以检查 NOx激活的改变，检测ROS，胞质和线粒体的变化！ nad（p）h 氧化还原和线粒体膜电位和线粒体超氧化物的指标。重点 这些研究是开发一种理解过程，以控制胞质和 线粒体NAD（P）H氧化还原和ROS产生与血管力的控制有关 一代。 AIM 3中的研究检查AIM 1和AIM 2中研究了多少个机制 在暴露于急性和慢性的其他项目中研究的动物的血管组织改变了 血管紧张素II的增加而没有血压升高，体内变化，糖尿病患者和 老化。