Nitric Oxide-Superoxide Interactions in Vascular Injury

描述(由申请人提供) 这一新的FIRCA应用程序中描述的实验目标旨在 血管内皮细胞发病的基本分子机制 高血糖和高脂血症过程中的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与培训 自由基生物学和医学方面的活动由研究人员在 阿拉巴马大学伯明翰医学院和伯明翰分校 乌拉圭蒙得维的亚共和国大学的美第奇那。 具体地说，父母赠款的主题是“依赖一氧化氮的氧化 肺损伤“解决了肺暴露于内源性辐射的假说 而外源性NO，面对氧化应激，会导致组织氧化 损害，将向一个新的重要方向扩展，通过解决 高血糖时线粒体衍生率增加的新概念 超氧化物(O2)与NO反应，降低其细胞信号功能，并 促进细胞毒性和促凋亡反应的形成 中间过亚硝酸根阴离子(ONOO)。这一假设提供了一个统一的 NO生物利用度降低的机制 高血糖，从而损害内皮依赖的血管扩张，以及 糖尿病血管内皮细胞的退化和血栓形成过程， 假定由ONOO介导的修改和释放触发 促凋亡的线粒体成分，如细胞色素c。来测试这一点 假设，从生化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)探讨 一氧化氮与线粒体超氧化物歧化反应 生物利用度和细胞凋亡信号，2)评估一氧化氮的作用 氧化物衍生氧化剂在高血糖对血管内皮细胞损伤中的作用。 因此，这些具体目标扩展了我们研究工作的核心主题 也就是说，NO信号被氧化应激有效地改变，并且经常 产生致病的次级介体。在本提案中，我们针对 首次发现线粒体衍生的O2和NO之间的相互作用，我们认为 在血管细胞功能障碍的发展过程中起关键作用 在糖尿病中观察到的损伤，从这个新的洞察力将揭示新的 治疗糖尿病的独特药理学方法的前景 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.