Nitric Oxide-Superoxide Interactions in Vascular Injury

描述（由申请人提供） 在这个新的FIRCA应用程序中描述的实验目标 血管内皮损伤的基本分子机制 在高血糖症过程中观察到细胞功能障碍和变性， 糖尿病的血管并发症它们也是 进一步扩大互利合作研究和培训， 自由基生物学和医学的研究人员分享的活动， 亚拉巴马大学伯明翰分校医学院和 乌拉圭蒙得维的亚大学医学院。 具体来说，主题的母基金“一氧化氮依赖的氧化 肺损伤”的假设，肺暴露于内源性 而外源性NO在氧化应激面前，导致组织氧化应激， 损害，将通过解决 一种新的概念，在高血糖期间， 超氧化物（O2）与NO反应，降低其细胞信号传导功能， 促进细胞毒性和促凋亡反应性的形成， 中间过氧亚硝酸根阴离子（ONOO）。这一假设提供了一个统一的 解释NO生物利用度降低的机制 高血糖，从而损害内皮依赖性血管舒张，以及 在糖尿病内皮上观察到的变性和血栓形成过程， 推测是由ONOO介导的修饰和释放 促凋亡线粒体组分如细胞色素C。为了验证这一 假设，从生物化学到细胞水平的一系列研究将 通过追求以下具体目标来颁布：1）探索的影响 一氧化氮与线粒体超氧化物对一氧化氮的反应 生物利用度和细胞凋亡信号传导，2）评估一氧化氮的作用 氧化物衍生的氧化剂在高血糖对血管内皮细胞的损伤中的作用。 因此，这些具体的目标扩展了我们研究工作的中心主题 也就是说，NO信号传导被氧化应激有效地修饰，并且通常 产生致病的次级介质。在本提案中，我们针对 第一次之间的相互作用，源于尿道O2和NO，我们认为 在血管细胞功能障碍的发展过程中至关重要， 损伤观察糖尿病，并从这一新的见解将揭示新的 独特的药物治疗糖尿病的前景 血管病变

DESCRIPTION (provided by applicant) The experimental goals described in this new FIRCA application address fundamental molecular mechanisms underlying the cause of vascular endothelial cell dysfunction and degeneration observed in the course of hyperglycemia and the vascular complications of diabetes. They also serve as the foundation for further expanding the mutually beneficial collaborative research and training activities in free radical biology and medicine shared by investigators at the University of Alabama at Birmingham School of Medicine and the Facultad de Medicina of the Universidad de La Republica in Montevideo, Uruguay. Specifically, the theme of the parent grant "Nitric Oxide-Dependent Oxidative Lung Injury" addressing the hypothesis that pulmonary exposure to endogenous and exogenous NO, in the face of oxidative stress, leads to tissue oxidative damage, will be expanded in a new and important direction by addressing the novel concept that during hyperglycemia enhanced rates of mitochondrial-derived superoxide (O2) react with NO, decreasing its cell signaling functions and promoting the formation of the cytotoxic and pro-apoptotic reactive intermediate peroxynitrite anion (ONOO). This hypothesis provides an unifying mechanism accounting for the decreased bioavailability of NO during hyperglycemia, thus impairing endothelial-dependent vasodilation, as well as the degenerative and thrombogenic processes observed at diabetic endothelium, postulated to be triggered by ONOO-mediated modification and release of pro-apoptotic mitochondrial components such as cytochrome c. To test this hypothesis, a series of studies ranging from biochemical to cellular level will be enacted by pursuing the following Specific Aims: 1) Explore the impact of nitric oxide reaction with mitochondrial superoxide on nitric oxide bioavailability and apoptotic signaling, 2) Evaluate the role of nitric oxide-derived oxidants in hyperglycemic injury to vascular endothelial cells. Thus, these specific aims extend a theme central to our research endeavors namely, that NO signaling is potently modified by oxidative stress and often yields pathogenic secondary mediators. In this proposal, we address for the first time the interplay between mitochondrial-derived O2 and NO, which we view to be critical during the development of the vascular cell dysfunction and injury observed in diabetes, and from this new insight will reveal new perspectives for unique pharmacological approaches to treat diabetic vasculopathy.