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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081750-05
Application #
7671263
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Srinivas, Pothur R
Project Start
2005-09-16
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2011-07-31
Support Year
5
Fiscal Year
2009
Total Cost
$349,641
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Jiang, Shuxia; Streeter, Jennifer; Schickling, Brandon M et al. (2014) Nox1 NADPH oxidase is necessary for late but not early myocardial ischaemic preconditioning. Cardiovasc Res 102:79-87
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Jagadeesha, Dammanahalli K; Takapoo, Maysam; Banfi, Botond et al. (2012) Nox1 transactivation of epidermal growth factor receptor promotes N-cadherin shedding and smooth muscle cell migration. Cardiovasc Res 93:406-13
Xu, Shaoping; Shriver, Amy S; Jagadeesha, Dammanahalli K et al. (2012) Increased expression of Nox1 in neointimal smooth muscle cells promotes activation of matrix metalloproteinase-9. J Vasc Res 49:242-8
Zimmerman, Matthew C; Takapoo, Maysam; Jagadeesha, Dammanahalli K et al. (2011) Activation of NADPH oxidase 1 increases intracellular calcium and migration of smooth muscle cells. Hypertension 58:446-53
Karrowni, Wassef; Dughman, Saadeddine; Hajj, Georges P et al. (2011) Statin therapy reduces growth of abdominal aortic aneurysms. J Investig Med 59:1239-43

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