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
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.
Arteriosclerosis, Thrombosis, and Vascular Biology
https://doi.org/10.1161/ATVBAHA.110.218669
HMGB1 Protein
Apolipoproteins E
Neutralizing Antibodies
Vascular Cell Adhesion Molecule-1
Chemokine CCL2
High Fat Diet
Cell Size
HMGB1
Kanellakis, P., Agrotis, A., Kyaw, T. S., Koulis, C., Ahrens, I., Mori, S., ... Bobik, A. (2011). High-Mobility Group Box Protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein E-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(2), 313-319. https://doi.org/10.1161/ATVBAHA.110.218669
High-Mobility Group Box Protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein E-deficient mice. / Kanellakis, Peter; Agrotis, Alex; Kyaw, Tin Soe; Koulis, Christine; Ahrens, Ingo; Mori, Shuji; Takahashi, Hideo K.; Liu, Keyue; Peter, Karlheinz; Nishibori, Masahiro; Bobik, Alex.
In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 31, No. 2, 02.2011, p. 313-319.
Kanellakis, P, Agrotis, A, Kyaw, TS, Koulis, C, Ahrens, I, Mori, S, Takahashi, HK, Liu, K, Peter, K, Nishibori, M & Bobik, A 2011, 'High-Mobility Group Box Protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein E-deficient mice', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 2, pp. 313-319. https://doi.org/10.1161/ATVBAHA.110.218669
Kanellakis P, Agrotis A, Kyaw TS, Koulis C, Ahrens I, Mori S et al. High-Mobility Group Box Protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein E-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 Feb;31(2):313-319. https://doi.org/10.1161/ATVBAHA.110.218669
Kanellakis, Peter ; Agrotis, Alex ; Kyaw, Tin Soe ; Koulis, Christine ; Ahrens, Ingo ; Mori, Shuji ; Takahashi, Hideo K. ; Liu, Keyue ; Peter, Karlheinz ; Nishibori, Masahiro ; Bobik, Alex. / High-Mobility Group Box Protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein E-deficient mice. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 ; Vol. 31, No. 2. pp. 313-319.
@article{43625ff50fb042cfacc8e65d5ba5f770,
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. 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.",
keywords = "atherosclerosis, HMGB1, macrophages",
author = "Peter Kanellakis and Alex Agrotis and Kyaw, {Tin Soe} and Christine Koulis and Ingo Ahrens and Shuji Mori and Takahashi, {Hideo K.} and Keyue Liu and Karlheinz Peter and Masahiro Nishibori and Alex Bobik",
doi = "10.1161/ATVBAHA.110.218669",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
T1 - High-Mobility Group Box Protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein E-deficient mice
AU - Kanellakis, Peter
AU - Agrotis, Alex
AU - Kyaw, Tin Soe
AU - Koulis, Christine
AU - Ahrens, Ingo
AU - Mori, Shuji
AU - Takahashi, Hideo K.
AU - Liu, Keyue
AU - Peter, Karlheinz
AU - Nishibori, Masahiro
AU - Bobik, Alex
N2 - 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.
AB - 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.
KW - HMGB1
KW - macrophages
U2 - 10.1161/ATVBAHA.110.218669
DO - 10.1161/ATVBAHA.110.218669
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
10.1161/ATVBAHA.110.218669