CCR5促进内皮祖细胞募集，并促进载脂蛋白E基因敲除小鼠动脉粥样硬化斑块的稳定。
CCR5 facilitates endothelial progenitor cell recruitment and promotes the stabilization of atherosclerotic plaques in ApoE-/- mice.
作者信息
Zhang Zhongwen, Dong Jianjun, Lobe Corrinne G, Gong Peiyun, Liu Ju, Liao Lin
机构信息
Department of Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, Shandong, 250014, China.
Department of Medicine, Qilu Hospital of Shandong University, Wenhua Road, Jinan, 250012, China.
出版信息
Stem Cell Res Ther. 2015 Mar 19;6(1):36. doi: 10.1186/s13287-015-0026-0.
INTRODUCTION
Unstable atherosclerotic plaques are prone to rupture, which leads to atherothrombosis. Endothelial progenitor cells (EPCs) are bone marrow-derived precursor cells that may repair vascular injury in atherosclerosis. Chemokine (C-C motif) receptor 5 (CCR5) promotes mobilization of EPCs. In this study, we investigated the therapeutic potential of CCR5-overexpressing EPCs on plaque stabilization in an apolipoprotein E (ApoE)-/- mouse model.
METHODS
The expression of CCR5 and its cognate ligand chemokine (C-C motif) ligand 5 (CCL5) was examined in atherosclerotic aortas of humans and mice by immunohistochemistry. Splenectomized ApoE-/- C57BL/6 J mice fed a high-fat diet for 24 weeks were intravenously injected with EPCs transfected with CCR5 overexpression lentivirus. The recruitment of EPCs over the atherosclerotic plaques was evaluated by immunofluorescence. The content of lipid, smooth muscle cells, monocytes/macrophages, and endothelial cells in atherosclerotic plaques was assayed by specific immunostaining. The serum levels of atherosclerosis-related inflammatory factors in ApoE-/- mice were measured by mouse atherosclerosis antibody array I.
RESULTS
CCR5 and CCL5 are highly expressed in atherosclerotic plaques in both humans and mice. The ApoE-/- mice with CCR5-overexpressing EPC treatment demonstrated a more stable plaque formation with enhanced recruitment of EPC, reduced lipid, and macrophage content in the atherosclerotic plaques. CCR5-overexpressing EPC treatment also increased the content of endothelial cells and nitric oxide production in the plaques. In addition, the serum levels of interleukin-3 (IL-3), IL-5, IL-6, IL-13, CD40, and tumor necrosis factor-alpha and the plaque contents of IL-6 and matrix metalloproteinase-9 were reduced in mice with CCR5-overexpressing EPC treatment.
CONCLUSIONS
These findings suggest that CCR5 is a novel therapeutic target in EPC treatment for stabilization of atherosclerotic plaques.
引言
不稳定的动脉粥样硬化斑块易于破裂，进而导致动脉粥样血栓形成。内皮祖细胞（EPCs）是源自骨髓的前体细胞，可能修复动脉粥样硬化中的血管损伤。趋化因子（C-C基序）受体5（CCR5）促进EPCs的动员。在本研究中，我们在载脂蛋白E（ApoE）基因敲除小鼠模型中研究了过表达CCR5的EPCs对斑块稳定的治疗潜力。
方法
通过免疫组织化学检测人类和小鼠动脉粥样硬化主动脉中CCR5及其同源配体趋化因子（C-C基序）配体5（CCL5）的表达。对24周高脂饮食喂养的脾切除ApoE基因敲除C57BL/6 J小鼠静脉注射过表达CCR5慢病毒转染的EPCs。通过免疫荧光评估EPCs在动脉粥样硬化斑块上的募集情况。通过特异性免疫染色测定动脉粥样硬化斑块中脂质、平滑肌细胞、单核细胞/巨噬细胞和内皮细胞的含量。通过小鼠动脉粥样硬化抗体芯片I检测ApoE基因敲除小鼠血清中动脉粥样硬化相关炎症因子的水平。
结果
CCR5和CCL5在人类和小鼠的动脉粥样硬化斑块中均高表达。过表达CCR5的EPCs治疗的ApoE基因敲除小鼠表现出更稳定的斑块形成，EPCs募集增加，动脉粥样硬化斑块中脂质和巨噬细胞含量减少。过表达CCR5的EPCs治疗还增加了斑块中内皮细胞的含量和一氧化氮的产生。此外，过表达CCR5的EPCs治疗的小鼠血清中白细胞介素-3（IL-3）、IL-5、IL-6、IL-13、CD40和肿瘤坏死因子-α水平以及斑块中IL-6和基质金属蛋白酶-9的含量降低。
结论
这些发现表明CCR5是EPCs治疗稳定动脉粥样硬化斑块的新治疗靶点。
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