Vitamin C, glutathione and NO action in humans

维生素 C、谷胱甘肽和 NO 对人体的作用

• 批准号: 6658448
• 负责人: Joseph A. Vita
• 金额: $ 26.22万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6658448
• 关键词: angiocardioultrasonography; antioxidants; ascorbate; atherosclerosis; cellular respiration; clinical research; dietary supplements; glutathione; guinea pigs; human subject; nitric oxide; nutrition related tag; oxidation reduction reaction; oxidative stress; plethysmography; prodrugs; superoxide dismutase; vasodilation

Loss of the vasodilator, anti-thrombotic, and anti-inflammatory actions of endothelial-l-derived NO (EDNO) in atherosclerosis contribute to the clinical manifestations of coronary artery disease. Increased vascular oxidative stress has been linked to impaired EDNO action in atherosclerosis. Specifically, oxidized LDL, increased production of superoxide anion, and decreased availability of cellular antioxidant species may all contribute to impaired EDNO action. Prior studies investigating interactions between antioxidant species may all contribute to impaired EDNO action. Prior studies investigating interactions between antioxidants and EDNO have focused principally on lipid- soluble and extracellular antioxidants. However, the importance of intracellular redox status for EDNO action has been much less well characterized. Ascorbic acid (AA) and glutathione (GSH) are the principal water-soluble antioxidants in cells. We recently demonstrated that AA treatment improves EDNO-action in patients with atherosclerosis. We recently demonstrated that EDNO action is improved by oxothiazolidine-4-carboxylic acid (OTC), a cysteine pro-drug that augments cellular GSH stores. The goal of this project is to investigate the importance of cellular redox status in EDNO bioactivity in humans with coronary atherosclerosis with particular emphasis of the roles played by AA and GSH. We will use well-established methods to assess EDNO- dependent vasodilation including high-resolution brachial ultrasound, intra-arterial agonist infusion with venous occlusion plethysmography in the forearm of quantitative angiography and Doppler ultrasound in the coronary artery. Cellular redox state will be manipulated by acute or chronic administration of AA, OTC, EUK-8, an intracellularly-effective superoxide dismutase mimic, or lipoic acid, a thiol compound that reverse mitochondrial decay. The effects of these agents on cellular redox status will be confirmed by examining AA and GSH concentrations in vascular tissue collected intra-operatively and blood cells from patients. These parameters will be correlated with vasomoter responses. Since loss of EDNO action may contribute to the pathophysiology of ischemic syndromes in atherosclerosis, these studies have the potential to provide important insights for the management of coronary artery disease.

失去血管扩张、抗血栓和抗炎作用 动脉粥样硬化中内皮-l 衍生的一氧化氮 (EDNO) 有助于 冠状动脉疾病的临床表现。血管增多 氧化应激与 EDNO 作用受损有关 动脉粥样硬化。具体来说，氧化低密度脂蛋白，增加产生 超氧阴离子和细胞抗氧化剂的可用性降低 物种可能都会导致 EDNO 作用受损。之前的研究 研究抗氧化剂物种之间的相互作用可能都有助于 EDNO 作用受损。先前的研究调查了相互作用 抗氧化剂和 EDNO 之间的研究主要集中在脂质 可溶性和细胞外抗氧化剂。然而，重要性 EDNO 作用的细胞内氧化还原状态不太好 特点。抗坏血酸（AA）和谷胱甘肽（GSH）是 细胞内主要的水溶性抗氧化剂。我们最近展示了 AA 治疗可改善患者的 EDNO 作用 动脉粥样硬化。我们最近证明 EDNO 作用得到改善 氧化噻唑烷-4-羧酸 (OTC)，一种半胱氨酸前药， 增加细胞谷胱甘肽储存。该项目的目标是调查 细胞氧化还原状态对人类 EDNO 生物活性的重要性 与冠状动脉粥样硬化，特别强调所发挥的作用 通过 AA 和 GSH。我们将使用完善的方法来评估 EDNO- 依赖性血管舒张，包括高分辨率肱骨超声， 动脉内注射激动剂并结合静脉阻塞体积描记术 前臂定量血管造影和多普勒超声检查 冠状动脉。细胞氧化还原状态将受到急性或 长期施用 AA、OTC、EUK-8，一种细胞内有效的药物 超氧化物歧化酶模拟物或硫辛酸，一种硫醇化合物，可逆转 线粒体衰变。这些药物对细胞氧化还原状态的影响 通过检查血管中的 AA 和 GSH 浓度来确认 术中收集的组织和患者的血细胞。这些 参数将与血管舒缩反应相关。自从失去 EDNO 作用可能有助于缺血性心脏病的病理生理学 动脉粥样硬化综合征，这些研究有可能提供 冠状动脉疾病治疗的重要见解。