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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1375.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Increased Expression of Glutathione Reductase in Macrophages Decreases Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor–Deficient Mice

Mu Qiao; Marta Kisgati; Jill M. Cholewa; Weifei Zhu; Eric J. Smart; Melanie S. Sulistio; Reto Asmis

From the Division of Nephrology (M.Q., R.A.), University of Texas Health Science Center at San Antonio and South Texas Veterans Health Care System, San Antonio, Tex; Department of Laboratory Medicine (M.K.), Kenezy Gyula Hospital, Debrecen, Hungary; Graduate Center for Nutritional Sciences (J.M.C.) and the Department of Pediatrics (E.J.S.), University of Kentucky, Lexington, Ky; University of Texas Southwestern Medical Center (W.Z.), Dallas, Tex; Division of Cardiology (M.S.S.), University of Texas Health Science Center at San Antonio, Tex.

Correspondence to Reto Asmis, Division of Nephrology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MSC 7882, San Antonio, TX 78229. E-mail asmis{at}uthscsa.edu

Objective— Thiol oxidative stress leads to macrophage dysfunction and cell injury, and has been implicated in the development of atherosclerotic lesions. We investigated if strengthening the glutathione-dependent antioxidant system in macrophages by overexpressing glutathione reductase (GR) decreases the severity of atherosclerosis.

Methods and Results— Bone marrow cells infected with retroviral vectors expressing either enhanced green fluorescent protein (EGFP) or an EGFP-fusion protein of cytosolic GR (GR^cyto-EGFP) or mitochondrial GR (GR^mito-EGFP) were transplanted into low-density lipoprotein receptor-deficient mice. Five weeks after bone marrow transplantation, animals were challenged with a Western diet for 10 weeks. No differences in either plasma cholesterol and triglyceride levels or peritoneal macrophage content were observed. However, mice reconstituted with either GR^cyto-EGFP or GR^mito-EGFP–expressing bone marrow had lesion areas (P<0.009) that were 32% smaller than recipients of EGFP-expressing bone marrow. In cultured macrophages, adenovirus-mediated overexpression of GR^cyto-EGFP or GR^mito-EGFP protected cells from mitochondrial hyperpolarization induced by oxidized low-density lipoprotein.

Conclusion— This study provides direct evidence that the glutathione-dependent antioxidant system in macrophages plays a critical role in atherogenesis, and suggests that thiol oxidative stress-induced mitochondrial dysfunction contributes to macrophage injury in atherosclerotic lesions.

Thiol oxidative stress leads to macrophage dysfunction and cell injury, and has been implicated in the development of atherosclerotic lesions. We show that overexpression of mitochondrial or cytosolic glutathione reductase in macrophages decreases the severity of atherosclerosis, providing direct evidence that the glutathione-dependent antioxidant system in macrophages plays a critical role in atherogenesis.

Key Words: atherosclerosis • glutathione • macrophage • oxidized low-density lipoprotein • oxidative stress

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