Increased expression of glutathione reductase in macrophages decreases atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice.
Arterioscler Thromb Vasc Biol
; 27(6): 1375-82, 2007 Jun.
Article
em En
| MEDLINE
| ID: mdl-17363688
ABSTRACT
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 ANDRESULTS:
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.
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Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
/
Estresse Oxidativo
/
Proteínas Relacionadas a Receptor de LDL
/
Aterosclerose
/
Glutationa
/
Glutationa Redutase
/
Macrófagos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article