High-Mobility Group Box Protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein E-deficient mice

Peter Kanellakis, Alex Agrotis, Tin Soe Kyaw, Christine Koulis, Ingo Ahrens, Shuji Mori, Hideo K. Takahashi, Keyue Liu, Karlheinz Peter, Masahiro Nishibori, Alex Bobik

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Objective-: High-mobility group box protein 1 (HMGB1) is a DNA-binding protein and cytokine highly expressed in atherosclerotic lesions, but its pathophysiological role in atherosclerosis is unknown. We investigated its role in the development of atherosclerosis in ApoE-/- mice. Methods and results-: Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet were administered a monoclonal anti-HMGB1 neutralizing antibody, and the effects on lesion size, immune cell accumulation, and proinflammatory mediators were assessed using Oil Red O, immunohistochemistry, and real-time polymerase chain reaction. As with human atherosclerotic lesions, lesions in ApoE-/- mice expressed HMGB1. Treatment with the neutralizing antibody attenuated atherosclerosis by 55%. Macrophage accumulation was reduced by 43%, and vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression was attenuated by 48% and 72%, respectively. CD11c+ dendritic cells were reduced by 65%, and the mature (CD83+) population was reduced by 60%. Treatment also reduced CD4+ cells by nearly 50%. mRNAs in lesions encoding tumor necrosis factor-α and interleukin-1β tended to be reduced. Mechanistically, HMGB1 stimulated macrophage migration in vitro and in vivo; in vivo, it markedly augmented the accumulation of F4/80+Gr-1(Ly-6C)+ macrophages and also increased F4/80+CD11b+ macrophage numbers. Conclusion-: HMGB1 exerts proatherogenic effects augmenting lesion development by stimulating macrophage migration, modulating proinflammatory mediators, and encouraging the accumulation of immune and smooth muscle cells.

Original languageEnglish
Pages (from-to)313-319
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number2
DOIs
Publication statusPublished - Feb 2011

Keywords

  • HMGB1
  • atherosclerosis
  • macrophages

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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