Glutathione Peroxidase & Redox State in Atherosclerosis

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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.