Glutathione Peroxidase & Redox State in Atherosclerosis

谷胱甘肽过氧化物酶

• 批准号: 7122935
• 负责人: FRANCIS J MILLER
• 金额: $ 36.01万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-16 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122935
• 关键词: NAD(P)H dehydrogenase; atherosclerosis; blood vessels; cytoprotection; enzyme activity; genetically modified animals; glutathione peroxidase; laboratory mouse; oxidation reduction reaction; pathologic process

DESCRIPTION (provided by applicant): Production of reactive oxygen species (ROS) and changes in the cellular redox environment regulate various aspects of cellular function. Previous studies of oxidative stress in vascular disease have focused on ROS generating systems. Little is known, however, regarding effects of the redox state of vascular cells on ROS signaling and cell function in vascular disease. Glutathione (GSH) is the most abundant redox buffer in the cell. The cytosolic enzyme glutathione peroxidase-1 (GPx-1) protects the cell against oxidant stress by utilizing GSH to reduce hydrogen peroxide and lipid peroxides. Oxidative stress, however, will inactivate GPx-1. Although decreased GPx-1 activity is a predictor of cardiovascular events in patients with coronary artery disease, it is not known whether GPx-1 activity directly contributes to the pathophysiology of atherosclerosis. The central hypothesis of this project is that changes in GPx-1 activity in the blood vessel are causally related to the progression of atherosclerosis via alterations in the activity of NADPH oxidase enzymes. The proposed studies are an extension of previous observations made by the investigators of NADPH oxidase-derived ROS in atherosclerosis. First, studies will test the hypothesis that effects of changes in GPx-1 activity on smooth muscle cells are mediated by hvdroperoxide-induced oxidative stress. Proposed studies will test the hypothesis that cellular responses to changes in GPx-1 activity are dependent on the duration of the change in cellular redox. Second, studies are proposed to determine if effects of reduction in GPx-1 activity on smooth muscle cells are mediated by expression of the NADPH oxidase subunits Nox1 and Nox4. Finally, studies are proposed to test the hypothesis that changes of GPx-1 activity in vivo affect progression of atherosclerosis and the expression of Nox enzymes. Information gained from these studies will provide a foundation for additional studies of redox status in vascular disease and potential novel therapeutic strategies to modify the progression of atherosclerosis in patients.

描述（由申请人提供）：活性氧（ROS）的产生和细胞氧化还原环境的变化调节细胞功能的各个方面。先前关于血管疾病中氧化应激的研究集中在ROS产生系统上。然而，关于血管细胞氧化还原状态对血管疾病中ROS信号传导和细胞功能的影响，知之甚少。谷胱甘肽（GSH）是细胞中最丰富的氧化还原缓冲液。胞质酶谷胱甘肽过氧化物酶-1（GPX-1）通过利用GSH减少过氧化氢和脂质过氧化氢来保护细胞免受氧化应激。但是，氧化应激将使GPX-1失活。尽管GPX-1活性的降低是冠状动脉疾病患者心血管事件的预测指标，但尚不清楚GPX-1活性是否直接有助于动脉粥样硬化的病理生理学。该项目的中心假设是，血管中GPX-1活性的变化通过改变NADPH氧化酶酶的活性而与动脉粥样硬化的进展有关。拟议的研究是由NADPH氧化酶衍生的ROS在动脉粥样硬化中进行的先前观察结果的扩展。首先，研究将检验以下假设：GPX-1活性变化对平滑肌细胞的影响是由Hvdroperoxide诱导的氧化应激介导的。提出的研究将检验以下假设：细胞对GPX-1活性变化的反应取决于细胞氧化还原的变化持续时间。其次，提出了研究以确定GPX-1活性降低对平滑肌细胞的影响是否通过表达NADPH氧化酶亚基NOX1和NOX4介导。最后，提出了研究以检验以下假设：体内GPX-1活性的变化会影响动脉粥样硬化的进展和NOX酶的表达。从这些研究中获得的信息将为血管疾病中的氧化还原状态以及潜在的新型治疗策略的额外研究提供基础，以改变患者动脉粥样硬化的进展。