title: Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Sussan
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jun
authors.forename: Rajesh
authors.initials: R
authors.lastname: Thimmulappa
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Maria
authors.initials: M
authors.lastname: Antero
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018955:CD36 Antigens / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D018955:CD36 Antigens; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse