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

Research output: Contribution to journalArticle

41 Scopus citations

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 languageEnglish (US)
Pages (from-to)1375-1382
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume27
Issue number6
DOIs
StatePublished - Jun 1 2007

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Keywords

  • Atherosclerosis
  • Glutathione
  • Macrophage
  • Oxidative stress
  • Oxidized low-density lipoprotein

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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