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 Citations (Scopus)

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 2007

Fingerprint

Glutathione Reductase
LDL Receptors
Macrophages
Sulfhydryl Compounds
Glutathione
Atherosclerosis
Oxidative Stress
Antioxidants
Bone Marrow
enhanced green fluorescent protein
Wounds and Injuries
Peritoneal Macrophages
Bone Marrow Transplantation
Adenoviridae
Bone Marrow Cells
Triglycerides
Cholesterol

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Increased expression of glutathione reductase in macrophages decreases atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice. / Qiao, Mu; Kisgati, Marta; Cholewa, Jill M.; Zhu, Weifei; Smart, Eric J.; Sulistio, Melanie S.; Asmis, Reto.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 27, No. 6, 06.2007, p. 1375-1382.

Research output: Contribution to journalArticle

Qiao, Mu ; Kisgati, Marta ; Cholewa, Jill M. ; Zhu, Weifei ; Smart, Eric J. ; Sulistio, Melanie S. ; Asmis, Reto. / Increased expression of glutathione reductase in macrophages decreases atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2007 ; Vol. 27, No. 6. pp. 1375-1382.
@article{1e6eb829e3f94ba68aa971881cacbe09,
title = "Increased expression of glutathione reductase in macrophages decreases atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice",
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.",
keywords = "Atherosclerosis, Glutathione, Macrophage, Oxidative stress, Oxidized low-density lipoprotein",
author = "Mu Qiao and Marta Kisgati and Cholewa, {Jill M.} and Weifei Zhu and Smart, {Eric J.} and Sulistio, {Melanie S.} and Reto Asmis",
year = "2007",
month = "6",
doi = "10.1161/ATVBAHA.107.142109",
language = "English (US)",
volume = "27",
pages = "1375--1382",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Increased expression of glutathione reductase in macrophages decreases atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice

AU - Qiao, Mu

AU - Kisgati, Marta

AU - Cholewa, Jill M.

AU - Zhu, Weifei

AU - Smart, Eric J.

AU - Sulistio, Melanie S.

AU - Asmis, Reto

PY - 2007/6

Y1 - 2007/6

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Glutathione

KW - Macrophage

KW - Oxidative stress

KW - Oxidized low-density lipoprotein

UR - http://www.scopus.com/inward/record.url?scp=34249288301&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34249288301&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.107.142109

DO - 10.1161/ATVBAHA.107.142109

M3 - Article

C2 - 17363688

AN - SCOPUS:34249288301

VL - 27

SP - 1375

EP - 1382

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 6

ER -