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: 7252866
• 负责人: Michael S Wolin
• 金额: $ 36.98万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252866
• 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)活性和亚基表达在控制介质释放方面具有重要作用， 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。目标1中的研究将定义以下因素的影响： 血管紧张素II、牵张、蛋白激酶C刺激物之间的相互作用对Nox氧化酶调节的途径 (PKC)和改变NAD（P）H对ROS的可用性和血管收缩功能的氧化还原调节。 没有血管疾病或内皮因子。系统研究的重点包括控制 细胞质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 代谢、氧化剂产生和氧化还原控制），以及这些系统对特定ROS和 氧化还原控制的信号机制，已知调节血管力的产生。研究目的2 研究Nox活性的变化如何控制内皮细胞释放NO、ROS和反应性NO衍生 种（RNS），以及内皮和NO供体药物衍生的RNS对研究的系统的影响， 目标1。重点将放在我们以前在牛冠状动脉中的信号研究的基础上， 由于p47 phox和Nox-2缺陷小鼠的可用性， Nox氧化酶的（gp 91 phox）亚基。新鲜分离的血管平滑肌细胞将通过 在不存在和存在NO供体的情况下进行荧光成像，以检查 通过检测ROS、胞质和线粒体的变化来改变Nox活化！NAD（P）H 氧化还原，以及线粒体膜电位和线粒体内超氧化物的指标。的焦点 这些研究是为了了解控制胞质和胞质之间相互作用的过程， 线粒体NAD（P）H氧化还原和ROS生成与血管力的控制有关 一代目标3中的研究检查了目标1和目标2中研究的机制中有多少是 在其他项目中研究的暴露于急性和慢性 血管紧张素II增加而不增加血压，体内压力改变，糖尿病和 衰老