High-Mobility Group Box Protein 1 Neutralization Reduces Development of Diet-Induced Atherosclerosis in Apolipoprotein E-Deficient Mice
High-Mobility Group Box Protein 1 Neutralization Reduces Development of Diet-Induced Atherosclerosis in Apolipoprotein E-Deficient Mice
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DOI：
10.1161/atvbaha.110.218669
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发表时间：
2011-02-01
影响因子：
8.7
通讯作者：
Bobik, Alex
中科院分区：
文献类型：
--
作者：
Kanellakis, Peter;Agrotis, Alex;Bobik, Alex
目的：高迁移率组盒蛋白1 （HMGB1）是一种在动脉粥样硬化病变中高表达的dna结合蛋白和细胞因子，但其在动脉粥样硬化中的病理生理作用尚不清楚。我们研究了它在ApoE-/-小鼠动脉粥样硬化发展中的作用。方法与结果：给高脂饲料喂养的载脂蛋白e缺陷（ApoE-/-）小鼠注射抗hmgb1单克隆中和抗体，采用油红O、免疫组织化学和实时聚合酶链反应评估其对病变大小、免疫细胞积累和促炎介质的影响。与人类动脉粥样硬化病变一样，ApoE-/-小鼠的病变表达HMGB1。用中和抗体治疗可使动脉粥样硬化减轻55%。巨噬细胞聚集减少43%，血管细胞粘附分子-1和单核细胞趋化蛋白-1表达分别减少48%和72%。CD11c+树突状细胞减少65%，成熟细胞（CD83+）减少60%。治疗还使CD4+细胞减少了近50%。病变中编码肿瘤坏死因子- α和白细胞介素-1 β的mrna倾向于减少。HMGB1在体外和体内刺激巨噬细胞迁移；在体内，它明显增加F4/80+Gr-1(Ly-6C)+巨噬细胞的积累，并增加F4/80+CD11b+巨噬细胞的数量。结论- hmgb1通过刺激巨噬细胞迁移、调节促炎介质、促进免疫细胞和平滑肌细胞的聚集，促进病变发展，具有促动脉粥样硬化作用。（中华动脉血管杂志，2011;31:313-319）
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-alpha and interleukin-1 beta 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. (Arterioscler Thromb Vasc Biol. 2011;31:313-319.)