Oxidants and Nitric Oxide in Coronary Vascular Function

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起着重要作用 血管内皮细胞及其调控血管平滑肌收缩功能的信号机制 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 Ang II、Stretch、蛋白激酶C刺激物相互作用调节NOx氧化酶的途径 (PKC)，并改变NAD(P)H对ROS的可用性和氧化还原调节血管收缩功能 没有血管疾病或血管内皮细胞因子。所研究的系统重点包括控制 胞浆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、氧化剂的产生和氧化还原控制)，以及这些系统对特定的ROS和 氧化还原控制的信号机制已知的调节血管力量的产生。AIM 2中的研究 研究NOx活性变化如何控制内皮细胞释放NO、ROS和反应性NO衍生 物种(RNS)，以及内皮和非供体药物衍生的RNS对系统的影响 目标1.重点将放在我们之前对牛冠状动脉和 由于p47Phox和NOx-2基因缺陷的小鼠的可用性，将这些研究扩展到小鼠的主动脉 (Gp91Phox)亚基。新鲜分离的血管平滑肌细胞将通过 荧光成像在没有和有无供体的情况下检查两者之间的关系 通过检测ROS、胞浆和线粒体的变化来检测NOx激活的变化！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示物。一个焦点 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生成与血管张力控制 一代。目标3中的研究考察了目标1和目标2中研究的机制中有多少是 在暴露于急性和慢性暴露的其他项目中研究的动物的血管组织中发生变化 血管紧张素II增加而不增加血压，体内血压变化，糖尿病患者和 衰老。

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.