on March 15, 2007
Published online before print March 15, 2007, doi: 10.1161/ATVBAHA.107.142109
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Submitted on October 27, 2006
Accepted on March 2, 2007
Increased Expression of Glutathione Reductase in Macrophages Decreases Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice
Mu Qiao ;
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.), University of Kentucky, Lexington, Ky; University of Texas Southwestern Medical Center (W.Z., E.J.S.), Dallas, Tex; Division of Cardiology (M.S.S.), University of Texas Health Science Center at San Antonio, Tex.
* To whom correspondence should be addressed. 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 EGFP or an EGFP-fusion protein of cytosolic GR (GRcyto-EGFP) or mitochondrial GR (GRmito-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 GRcyto-EGFP or GRmito-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 GRcyto-EGFP or GRmito-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.
Key words: atherosclerosis • glutathione • macrophage • oxidized low-density lipoprotein • oxidative stress
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