XANTHINE OXIDASE AND VASCULAR DYSFUNCTION

黄嘌呤氧化酶和血管功能障碍

• 批准号: 2597175
• 负责人: C Roger WHITE
• 金额: $ 5.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2597175
• 关键词: atherosclerosis; blood lipoprotein; cellular pathology; disease /disorder etiology; enzyme activity; free radical oxygen; hypercholesterolemia; laboratory rabbit; molecular pathology; mucopolysaccharides; oxidative stress; protein binding; superoxide dismutase; superoxides; tissue /cell culture; vascular endothelium; vasomotion; xanthine oxidase

DESCRIPTION (Adapted from applicants' abstract) Reactive oxygen species induce changes in vascular function in conditions such as stroke, hypertension and atherosclerosis. The nature and complexity of lesion development in atherosclerosis suggest that the disease may have several etiologies. The generation of free radicals is associated with alterations in both vascular reactivity and lipoprotein metabolism. The studies proposed in this application are designed to provide new information concerning oxidant-induced damage in the vessel wall. It is hypothesized that impaired blood vessel function in hypercholesterolemic rabbits is due to the modification of nitric oxide (NO) by superoxide anion (O2-), leading to the production of the potent oxidant peroxynitrite (ONOO-). Reactive oxygen species are generated under normal physiological conditions, with native antioxidant scavengers minimizing oxidant-mediated injury. An imbalance in antioxidant defense mechanisms and changes in cellular metabolic processes then contributes to the development and progression of atherosclerotic disease. The studies outlined in this application are designed to provide new information describing the cellular mechanisms involved in these free radical reactions, namely that free radical injury in blood vessels of hypercholesterolemic rabbits is linked to the binding and concentration of xanthine oxidase (XO) at glycosaminoglycan (GAG) sites on the surface of endothelial cells and in the interstitial space. The hypothesis to be tested in this application is that GAG-bound XO is an important source of O2-, thus ONOO- formation, and contributes to the oxidative component of hypercholesterolemia. GAG function or expression may be altered by hyperlipidemia, thereby facilitating incorporation of lipoproteins in the vessel wall as well as serving as a site for XO binding and incorporation, influencing changes in the vasculature and playing an important role in the pathological events associated with hyper-cholesterolemia. (End of Abstract)

描述 （改编自申请人摘要）活性氧引起的变化 在中风、高血压和 动脉粥样硬化 病变发展的性质和复杂性 动脉粥样硬化表明该疾病可能有几种病因。 的 自由基的产生与两种血管 反应性和脂蛋白代谢。 本报告中提出的研究 应用程序旨在提供有关 氧化剂引起的血管壁损伤。 据推测， 高胆固醇血症兔的血管功能是由于 超氧阴离子（O2-）修饰一氧化氮（NO），导致 产生强氧化剂过氧亚硝酸盐（ONOO-）。 活性氧 物种是在正常生理条件下产生的， 抗氧化剂清除剂，最大限度地减少氧化剂介导的损伤。 的不平衡 抗氧化防御机制和细胞代谢过程的变化 然后促进动脉粥样硬化的发展和进展 疾病 本申请中概述的研究旨在提供 新的信息描述参与这些自由的细胞机制 自由基反应，即血管中的自由基损伤， 高胆固醇血症的兔子与 黄嘌呤氧化酶（XO）在糖胺聚糖（GAG）的网站上的表面 内皮细胞和间质空间中。 假设是 在该应用中测试的是，GAG结合的XO是 O2-，从而ONOO-形成，并有助于氧化组分的 高胆固醇血症。 GAG功能或表达可通过以下方式改变 高脂血症，从而促进脂蛋白掺入 血管壁以及作为XO结合和掺入的位点， 影响血管系统的变化，并在 与高胆固醇血症相关的病理学事件。 (End的 摘要）