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 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-EGFP) or mitochondrial GR (GR-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-EGFP or GR-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-EGFP or GR-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.
Original language | English (US) |
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Pages (from-to) | 1375-1382 |
Number of pages | 8 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 27 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2007 |
Keywords
- Atherosclerosis
- Glutathione
- Macrophage
- Oxidative stress
- Oxidized low-density lipoprotein
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine