Glutathione Peroxidase & Redox State in Atherosclerosis

谷胱甘肽过氧化物酶

• 批准号: 6962111
• 负责人: FRANCIS J MILLER
• 金额: $ 36.88万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6962111
• 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。先前对血管疾病中氧化应激的研究主要集中在ROS生成系统上。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，我们知之甚少。谷胱甘肽（GSH）是细胞中最丰富的氧化还原缓冲物质。胞质酶谷胱甘肽过氧化物酶-1 （GPx-1）通过利用谷胱甘肽还原过氧化氢和脂质过氧化物来保护细胞免受氧化应激。然而，氧化应激会使GPx-1失活。虽然GPx-1活性降低是冠状动脉疾病患者心血管事件的预测因子，但目前尚不清楚GPx-1活性是否直接参与动脉粥样硬化的病理生理。该项目的中心假设是血管中GPx-1活性的变化通过改变NADPH氧化酶的活性与动脉粥样硬化的进展有因果关系。提出的研究是先前研究人员对动脉粥样硬化中NADPH氧化酶衍生的ROS的观察的延伸。首先，研究将验证GPx-1活性变化对平滑肌细胞的影响是由过氧化氢诱导的氧化应激介导的这一假设。拟议的研究将验证一个假设，即细胞对GPx-1活性变化的反应取决于细胞氧化还原变化的持续时间。其次，研究人员提出确定GPx-1活性降低对平滑肌细胞的影响是否通过NADPH氧化酶亚基Nox1和Nox4的表达介导。最后，提出了验证体内GPx-1活性变化影响动脉粥样硬化进展和Nox酶表达的假设。从这些研究中获得的信息将为血管疾病中氧化还原状态的进一步研究和潜在的新治疗策略提供基础，以改变患者动脉粥样硬化的进展。