Increased expression of glutathione reductase in macrophages decreases atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice.
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.


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.


CONCLUSIONS
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.
Qiao
Mu
M
Division of Nephrology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Kisgati
Marta
M
Cholewa
Jill M
JM
Zhu
Weifei
W
Smart
Eric J
EJ
Sulistio
Melanie S
MS
Asmis
Reto
R
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D001854:Bone Marrow Cells / Q000201:enzymology; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D004041:Dietary Fats; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology; D018384:Oxidative Stress; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012190:Retroviridae / Q000235:genetics; D012720:Severity of Illness Index; D013997:Time Factors; D014161:Transduction, Genetic
D004041:Dietary Fats; D026502:LDL-Receptor Related Proteins; D008077:Lipoproteins, LDL; D011993:Recombinant Fusion Proteins; C099252:oxidized low density lipoprotein; D005980:Glutathione Reductase; D005978:Glutathione