title: The absence of macrophage Nrf2 promotes early atherogenesis.
abstract: OBJECTIVE
  The loss of nuclear factor E2-related factor 2 (Nrf2) has been shown to protect against atherogenesis in apoE-deficient mice. The mechanism by which Nrf2 deficiency affords atheroprotection in this model is currently unknown, but combined systemic and local vascular effects on lesion macrophages have been proposed. We investigated the effect of bone marrow-specific loss of Nrf2 on early atherogenesis in low-density lipoprotein (LDL) receptor-deficient (LDLR(-/-)) mice, and assessed the effect of Nrf2 on cellular accumulation of modified LDLs and the expression of inflammatory markers in macrophages.
  
  
  RESULTS
  The effect of bone marrow-specific loss of Nrf2 on atherogenesis was studied using bone marrow transplantation of wild-type (WT) or Nrf2(-/-) bone marrow to LDLR(-/-) mice. Mice transplanted with Nrf2(-/-) bone marrow and fed a high-fat diet for 6 weeks exhibited significantly larger atherosclerotic lesions than WT bone marrow transplanted mice. Moreover, in thioglycollate-elicited Nrf2(-/-) macrophages, the uptake of acetylated and malondialdehyde-modified LDLs was increased in comparison with WT controls, with the concomitant increase in the expression of scavenger receptor A and toll-like receptor 4. In addition, the expression of pro-inflammatory monocyte chemoattractant protein-1 and interleukin-6 were increased in Nrf2(-/-) vs. WT macrophages.
  
  
  CONCLUSIONS
  Nrf2 deficiency specific to bone marrow-derived cells aggravates atherosclerosis in LDLR(-/-) mice. Furthermore, the loss of Nrf2 in macrophages enhances foam cell formation and promotes the pro-inflammatory phenotype.
authors: Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, Kuopio FIN-70211, Finland.
authors: Anna-Kaisa
authors: AK
authors: Ruotsalainen
authors: Matias
authors: M
authors: Inkala
authors: Mervi E
authors: ME
authors: Partanen
authors: Jari P
authors: JP
authors: Lappalainen
authors: Emilia
authors: E
authors: Kansanen
authors: Petri I
authors: PI
authors: Mäkinen
authors: Suvi E
authors: SE
authors: Heinonen
authors: Heidi M
authors: HM
authors: Laitinen
authors: Janne
authors: J
authors: Heikkilä
authors: Tero
authors: T
authors: Vatanen
authors: Sohvi
authors: S
authors: Hörkkö
authors: Masayuki
authors: M
authors: Yamamoto
authors: Seppo
authors: S
authors: Ylä-Herttuala
authors: Matti
authors: M
authors: Jauhiainen
authors: Anna-Liisa
authors: AL
authors: Levonen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology*; D018932:Chemokine CCL2 / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D011973:Receptors, LDL / Q000502:physiology; D051116:Receptors, Scavenger / Q000032:analysis
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011973:Receptors, LDL; D051116:Receptors, Scavenger; D002784:Cholesterol