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PMID: 19023427 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice.

PloS one ·Vol. 3 ·No. 11 ·2008-00-00 ·Pages e3791

Sussan TE, Jun J, Thimmulappa R, Bedja D, Antero M, Gabrielson KL, Polotsky VY, Biswal S

Abstract

Oxidative stress and inflammation are two critical factors that drive the formation of plaques in atherosclerosis. Nrf2 is a redox-sensitive transcription factor that upregulates a battery of antioxidative genes and cytoprotective enzymes that constitute the cellular response to oxidative stress. Our previous studies have shown that disruption of Nrf2 in mice (Nrf2(-/-)) causes increased susceptibility to pulmonary emphysema, asthma and sepsis due to increased oxidative stress and inflammation. Here we have tested the hypothesis that disruption of Nrf2 in mice causes increased atherosclerosis. To investigate the role of Nrf2 in the development of atherosclerosis, we crossed Nrf2(-/-) mice with apoliporotein E-deficient (ApoE(-/-)) mice. ApoE(-/-) and ApoE(-/-)Nrf2(-/-) mice were fed an atherogenic diet for 20 weeks, and plaque area was assessed in the aortas. Surprisingly, ApoE(-/-)Nrf2(-/-) mice exhibited significantly smaller plaque area than ApoE(-/-) controls (11.5% vs 29.5%). This decrease in plaque area observed in ApoE(-/-)Nrf2(-/-) mice was associated with a significant decrease in uptake of modified low density lipoproteins (AcLDL) by isolated macrophages from ApoE(-/-)Nrf2(-/-) mice. Furthermore, atherosclerotic plaques and isolated macrophages from ApoE(-/-)Nrf2(-/-) mice exhibited decreased expression of the scavenger receptor CD36. Nrf2 is pro-atherogenic in mice, despite its antioxidative function. The net pro-atherogenic effect of Nrf2 may be mediated via positive regulation of CD36. Our data demonstrates that the potential effects of Nrf2-targeted therapies on cardiovascular disease need to be investigated.

MeSH Terms
Animals Antioxidants/metabolism Apolipoproteins E/deficiency,genetics,metabolism Atherosclerosis/etiology,genetics,metabolism,prevention & control CD36 Antigens/metabolism Diet, Atherogenic Disease Models, Animal Female Male Mice Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2/deficiency,genetics,metabolism Oxidative Stress
Chemicals
Antioxidants Apolipoproteins E CD36 Antigens NF-E2-Related Factor 2 Nfe2l2 protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Sussan Thomas E
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
Jun Jonathan
Thimmulappa Rajesh
Bedja Djahida
Antero Maria
Gabrielson Kathleen L
Polotsky Vsevolod Y
Biswal Shyam
References (36)
36 references, click to expand
  1. The antioxidant butylated hydroxytoluene protects against atherosclerosis.
    Arterioscler Thromb. 1991 Jan-Feb;11(1):15-22 PMID: 1987993
  2. Effects of long-term daily low-dose supplementation with antioxidant vitamins and minerals on structure and function of large arteries.
    Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1485-91 PMID: 15217803
  3. CD36 deficiency in mice impairs lipoprotein lipase-mediated triglyceride clearance.
    J Lipid Res. 2005 Oct;46(10):2175-81 PMID: 16024917
  4. Nrf2 regulates the alternative first exons of CD36 in macrophages through specific antioxidant response elements.
    Arch Biochem Biophys. 2008 Sep 1;477(1):139-45 PMID: 18585365
  5. Serum glutathione in adolescent males predicts parental coronary heart disease.
    Circulation. 1999 Nov 30;100(22):2244-7 PMID: 10577998
  6. Atherosclerosis--an inflammatory disease.
    N Engl J Med. 1999 Jan 14;340(2):115-26 PMID: 9887164
  7. Role of oxidized LDL and antioxidants in atherosclerosis.
    Adv Exp Med Biol. 1995;369:39-48 PMID: 7598015
  8. Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice.
    Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1529-35 PMID: 10845868
  9. Induction of glutathione synthesis in macrophages by oxidized low-density lipoproteins is mediated by consensus antioxidant response elements.
    Circ Res. 2003 Mar 7;92(4):386-93 PMID: 12600891
  10. Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice.
    J Clin Invest. 2002 May;109(10):1381-9 PMID: 12021254
  11. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.
    J Clin Invest. 1997 Sep 1;100(5):1209-16 PMID: 9276739
  12. Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E.
    Circ Res. 2004 Nov 26;95(11):1075-81 PMID: 15528470
  13. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.
    J Clin Invest. 2000 Apr;105(8):1049-56 PMID: 10772649
  14. Antioxidants and the bioactivity of endothelium-derived nitric oxide.
    Cardiovasc Res. 2000 Aug 18;47(3):426-35 PMID: 10963716
  15. Vascular effects following homozygous disruption of p47(phox) : An essential component of NADPH oxidase.
    Circulation. 2000 Mar 21;101(11):1234-6 PMID: 10725280
  16. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis.
    J Clin Invest. 2006 Apr;116(4):984-95 PMID: 16585964
  17. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
    Circulation. 2002 Dec 17;106(25):3143-421 PMID: 12485966
  18. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.
    J Exp Med. 2005 Jul 4;202(1):47-59 PMID: 15998787
  19. Hemodynamic changes in apolipoprotein E-knockout mice.
    Am J Physiol Heart Circ Physiol. 2000 Nov;279(5):H2326-34 PMID: 11045969
  20. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway.
    Annu Rev Pharmacol Toxicol. 2007;47:89-116 PMID: 16968214
  21. Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling.
    FASEB J. 2003 Sep;17(12):1759-61 PMID: 12958201
  22. p47phox is required for atherosclerotic lesion progression in ApoE(-/-) mice.
    J Clin Invest. 2001 Nov;108(10):1513-22 PMID: 11714743
  23. Increased macrophage glutathione content reduces cell-mediated oxidation of LDL and atherosclerosis in apolipoprotein E-deficient mice.
    Atherosclerosis. 2002 Jul;163(1):17-28 PMID: 12048118
  24. Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice.
    J Lipid Res. 1995 Nov;36(11):2320-8 PMID: 8656070
  25. Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N,N'-diphenyl-phenylenediamine.
    J Clin Invest. 1992 Jun;89(6):1885-91 PMID: 1601995
  26. Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism.
    J Biol Chem. 2003 Jan 10;278(2):703-11 PMID: 12370194
  27. Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal.
    Circ Res. 2004 Mar 19;94(5):609-16 PMID: 14752028
  28. Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells.
    J Biol Chem. 2005 Jul 22;280(29):27244-50 PMID: 15917255
  29. Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS).
    Circulation. 2002 Sep 17;106(12):1453-9 PMID: 12234947
  30. Lipid peroxidation, isoprostanes and vascular damage.
    Pharmacol Rep. 2006;58 Suppl:57-68 PMID: 17332673
  31. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice.
    J Clin Invest. 2004 Nov;114(9):1248-59 PMID: 15520857
  32. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.
    Proc Natl Acad Sci U S A. 1987 Nov;84(21):7725-9 PMID: 3478721
  33. Dietary approach to attenuate oxidative stress, hypertension, and inflammation in the cardiovascular system.
    Proc Natl Acad Sci U S A. 2004 May 4;101(18):7094-9 PMID: 15103025
  34. The role of oxidized lipoproteins in atherogenesis.
    Free Radic Biol Med. 1996;20(5):707-27 PMID: 8721615
  35. 12/15-Lipoxygenase gene disruption and vitamin E administration diminish atherosclerosis and oxidative stress in apolipoprotein E deficient mice through a final common pathway.
    Prostaglandins Other Lipid Mediat. 2005 Dec;78(1-4):185-93 PMID: 16303615
  36. Role of oxidative modifications in atherosclerosis.
    Physiol Rev. 2004 Oct;84(4):1381-478 PMID: 15383655
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0003791
Published
2008-00-00
Epub
2008-00-21
Pages
e3791
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2582492
Subset
IM
Grants
NIEHS NIH HHS · P50ES015903 · United States
NIEHS NIH HHS · P50 ES015903 · United States
NIEHS NIH HHS · ES07141 · United States
NHLBI NIH HHS · R01 HL081205 · United States
NHLBI NIH HHS · P50 HL084945 · United States
NHLBI NIH HHS · HL080105 · United States
NHLBI NIH HHS · R01 HL080105 · United States
NHLBI NIH HHS · P50HL084945 · United States
NHLBI NIH HHS · HL081205 · United States
NIEHS NIH HHS · T32 ES007141 · United States
NHLBI NIH HHS · T32 HL07534 · United States
NHLBI NIH HHS · T32 HL007534 · United States
External Links
PubMed source DOI: 10.1371/journal.pone.0003791 PMC Full Text View journal details
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