The absence of macrophage Nrf2 promotes early atherogenesis

Anna Kaisa Ruotsalainen, Matias Inkala, Mervi E. Partanen, Jari P. Lappalainen, Emilia Kansanen, Petri I. Mäkinen, Suvi E. Heinonen, Heidi M. Laitinen, Janne Heikkilä, Tero Vatanen, Sohvi Hörkkö, Masayuki Yamamoto, Seppo Ylä-Herttuala, Matti Jauhiainen, Anna Liisa Levonen

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

Abstract

Aims 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.Methods and resultsThe 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. ConclusionNrf2 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.

Original languageEnglish
Pages (from-to)107-115
Number of pages9
JournalCardiovascular Research
Volume98
Issue number1
DOIs
Publication statusPublished - 2013 Apr 1

Keywords

  • Atherosclerosis
  • Bone marrow transplantation
  • Macrophage
  • Nrf2

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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