Glutaredoxin (Grx) is an important regulator of redox signaling and a key enzyme of the glutathione- dependent antioxidant system, which protects cells against oxidative injury. Numerous studies provide evidence that macrophage injury and cell death are major factors in the development of atherosclerotic lesions. Although free radicals and oxidative stress play a central role in atherogenesis, the impact of Grx on macrophage injury and the development and progression of atherosclerotic lesions has not been studied. The mechanisms underlying macrophage injury and cell death in vivo are unclear. Electron microscopy studies indicate that in human atherosclerotic lesions, the predominant mode of cell death is not apoptosis but oncosis, which is associated with an intense inflammatory response and hence with atherosclerotic lesion progression. Recently we demonstrated that in human monocyte-derived macrophages oxidized LDL (OxLDL) promotes cell death in a caspase-independent process resembling oncosis. We went on to show that OxLDL-induced macrophage death involves mitochondrial dysfunction and is mediated by peroxyl radical formation but that ROS formation alone cannot explain OxLDL cytotoxicity. Our preliminary data now demonstrate that OxLDL also promotes the massive depletion of reduced glutathione and to a lesser extent, of glutathione disulfide. This depletive process results in the collapse of the glutathione/glutathione disulfide ratio, a condition that favors the formation of mixed disulfides between reactive protein thiols and glutathione in a reaction referred to as protein-S-glutathionylation. Our studies show that thiol oxidative stress and protein-S-glutathionylation induced by OxLDL promote macrophage death. siRNA-mediated inhibition of Grx, the enzyme responsible for the degluathionylation of proteins, potentiated OxLDL-induced macrophage injury, indicating that Grx is required to protect macrophages from OxLDL-induced cell death. Because macrophage death appears to be a major contributing factor to the development and progression of atherosclerotic lesions, increasing the macrophage's protection against pathophysiological protein-S- glutathionylation likely will not only prevent macrophage death but may also decrease the severity of atherosclerosis. The proposed studies will test this hypothesis and examine possible molecular mechanisms of Grx-mediated protection of macrophages from mitochondrial dysfunction and cell death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070963-08
Application #
7805605
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Fleg, Jerome
Project Start
2002-08-01
Project End
2011-08-30
Budget Start
2010-05-01
Budget End
2011-08-30
Support Year
8
Fiscal Year
2010
Total Cost
$440,792
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Betts-Obregon, B S; Mondragon, A A; Mendiola, A S et al. (2016) TGF? induces BIGH3 expression and human retinal pericyte apoptosis: a novel pathway of diabetic retinopathy. Eye (Lond) 30:1639-1647
Zamora, D A; Downs, K P; Ullevig, S L et al. (2015) Glutaredoxin 2a overexpression in macrophages promotes mitochondrial dysfunction but has little or no effect on atherogenesis in LDL-receptor null mice. Atherosclerosis 241:69-78
Mondragon, Albert A; Betts-Obregon, Brandi S; Moritz, Robert J et al. (2015) BIGH3 protein and macrophages in retinal endothelial cell apoptosis. Apoptosis 20:29-37
Tavakoli, Sina; Zamora, Debora; Ullevig, Sarah et al. (2013) Bioenergetic profiles diverge during macrophage polarization: implications for the interpretation of 18F-FDG PET imaging of atherosclerosis. J Nucl Med 54:1661-7
Ullevig, Sarah; Zhao, Qingwei; Lee, Chi Fung et al. (2012) NADPH oxidase 4 mediates monocyte priming and accelerated chemotaxis induced by metabolic stress. Arterioscler Thromb Vasc Biol 32:415-26
Kim, Hong Seok; Ullevig, Sarah L; Zamora, Debora et al. (2012) Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment. Proc Natl Acad Sci U S A 109:E2803-12
Liu, Meilian; Xiang, Ruihua; Wilk, Sarah Ann et al. (2012) Fat-specific DsbA-L overexpression promotes adiponectin multimerization and protects mice from diet-induced obesity and insulin resistance. Diabetes 61:2776-86
Tavakoli, Sina; Asmis, Reto (2012) Reactive oxygen species and thiol redox signaling in the macrophage biology of atherosclerosis. Antioxid Redox Signal 17:1785-95
Asmis, Reto (2011) ""Topical"" HDL for vein grafts: a new solution to an old problem? Atherosclerosis 214:259-60
Ullevig, Sarah L; Zhao, Qingwei; Zamora, Debora et al. (2011) Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis. Atherosclerosis 219:409-16

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