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The absence of macrophage Nrf2 promotes early atherogenesis

Anna-Kaisa Ruotsalainen1, Matias Inkala, Mervi E Partanen

  • 1Department of Biotechnology and Molecular Medicine, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, Kuopio FIN-70211, Finland.

Cardiovascular Research
|January 24, 2013
PubMed
Abstract

Insights

Loss of nuclear factor E2-related factor 2 (Nrf2) in bone marrow cells worsens atherosclerosis. Nrf2 deficiency in macrophages increases modified LDL uptake and inflammation, promoting foam cell formation.

Area of Science:

  • Cardiovascular Research
  • Immunology
  • Molecular Biology

Background:

  • Nuclear factor E2-related factor 2 (Nrf2) plays a role in protecting against atherosclerosis.
  • The precise mechanisms of Nrf2's protective effects, particularly in macrophages, are not fully understood.
  • Previous studies suggest both systemic and local vascular impacts of Nrf2 deficiency.

Purpose of the Study:

  • To investigate the impact of bone marrow-specific Nrf2 deficiency on early atherosclerosis development.
  • To determine how Nrf2 influences the uptake of modified low-density lipoproteins (LDLs) by macrophages.
  • To assess the effect of Nrf2 on the expression of inflammatory markers in macrophages.

Main Methods:

  • Utilized bone marrow transplantation in low-density lipoprotein receptor-deficient (LDLR(-/-)) mice, transplanting either wild-type (WT) or Nrf2-deficient (Nrf2(-/-)) bone marrow.
  • Administered a high-fat diet for 6 weeks to induce atherosclerosis.
  • Analyzed atherosclerotic lesion size, modified LDL uptake by macrophages, and expression of scavenger receptors and inflammatory markers.

Main Results:

  • Mice receiving Nrf2(-/-) bone marrow exhibited significantly larger atherosclerotic lesions compared to WT controls.
  • Nrf2(-/-) macrophages showed increased uptake of acetylated and malondialdehyde-modified LDLs.
  • Expression of scavenger receptor A, toll-like receptor 4, monocyte chemoattractant protein-1, and interleukin-6 was elevated in Nrf2(-/-) macrophages.

Conclusions:

  • Bone marrow-specific Nrf2 deficiency exacerbates atherosclerosis in LDLR(-/-) mice.
  • Loss of Nrf2 in macrophages enhances foam cell formation, a key process in atherogenesis.
  • Nrf2 deficiency promotes a pro-inflammatory phenotype in macrophages, contributing to disease progression.

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