title: High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein e-deficient mice.
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.
  
  
  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.
  
  
  CONCLUSIONS
  HMGB1 exerts proatherogenic effects augmenting lesion development by stimulating macrophage migration, modulating proinflammatory mediators, and encouraging the accumulation of immune and smooth muscle cells.
authors.affiliation: BakerIDI Heart and Diabetes Institute, St Kilda Rd. Central, Melbourne, Victoria 8008, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Kanellakis
authors.forename: Alex
authors.initials: A
authors.lastname: Agrotis
authors.forename: Tin Soe
authors.initials: TS
authors.lastname: Kyaw
authors.forename: Christine
authors.initials: C
authors.lastname: Koulis
authors.forename: Ingo
authors.initials: I
authors.lastname: Ahrens
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.forename: Hideo K
authors.initials: HK
authors.lastname: Takahashi
authors.forename: Keyue
authors.initials: K
authors.lastname: Liu
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
authors.forename: Alex
authors.initials: A
authors.lastname: Bobik
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1