Cheng Wen-Lin, Yang Yang, Zhang Xiao-Jing, Guo Junhong, Gong Jun, Gong Fu-Han, She Zhi-Gang, Huang Zan, Xia Hao, Li Hongliang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
The Institute of Model Animals of Wuhan University, Wuhan, China.
J Am Heart Assoc. 2017 Feb 20;6(2):e004690. doi: 10.1161/JAHA.116.004690.
Dickkopf-3 (DKK3) is a negative regulator of the Wnt/β-catenin signaling pathway, which is involved in inflammation. However, little is known about the relationship between DKK3 expression and the progression of atherosclerosis. The aim of the present study was to define the role of DKK3 and its potential mechanism in the development of atherosclerosis.
Immunofluorescence analysis showed that DKK3 was strongly expressed in macrophages of atherosclerotic plaques from patients with coronary heart disease and in hyperlipidemic mice. The expression level was significantly increased in atherogenesis. DKK3ApoE mice exhibited a significant decrease in atherosclerotic lesions in the entire aorta, aortic sinus, and brachiocephalic arteries. Transplantation of bone marrow from DKK3ApoE mice into lethally irradiated ApoE recipients resulted in a reduction of atherosclerotic lesions, compared with the lesions in recipients transplanted with ApoE donor cells, suggesting that the effect of DKK3 deficiency was largely mediated by bone marrow-derived cells. A reduction in the necrotic core size, accompanied by increased collagen content and smooth muscle cells and decreased accumulation of macrophages and lipids, contributed to the stability of plaques in DKK3ApoE mice. Furthermore, multiple proinflammatory cytokines exhibited marked decreases in DKK3ApoE mice. Finally, we observed that DKK3 ablation increased β-catenin expression in the nuclei of macrophages both in vivo and in vitro.
DKK3 expression in macrophages is involved in the pathogenesis of atherosclerosis through modulation of inflammation and inactivation of the Wnt/β-catenin pathway.
Dickkopf-3（DKK3）是Wnt/β-连环蛋白信号通路的负调节因子，该信号通路参与炎症反应。然而，关于DKK3表达与动脉粥样硬化进展之间的关系知之甚少。本研究的目的是确定DKK3在动脉粥样硬化发生发展中的作用及其潜在机制。
免疫荧光分析显示，DKK3在冠心病患者动脉粥样硬化斑块的巨噬细胞以及高脂血症小鼠中强烈表达。在动脉粥样硬化形成过程中，其表达水平显著升高。DKK3基因敲除的载脂蛋白E（ApoE）小鼠在整个主动脉、主动脉窦和头臂动脉中的动脉粥样硬化病变显著减少。将DKK3基因敲除的ApoE小鼠的骨髓移植到经致死剂量照射的ApoE受体小鼠体内，与移植ApoE供体细胞的受体小鼠相比，动脉粥样硬化病变减少，这表明DKK3缺乏的影响主要由骨髓来源细胞介导。坏死核心大小减小，同时胶原含量、平滑肌细胞增加，巨噬细胞和脂质积累减少，有助于DKK3基因敲除的ApoE小鼠斑块的稳定性。此外，多种促炎细胞因子在DKK3基因敲除的ApoE小鼠中显著降低。最后，我们观察到，在体内外，DKK3基因敲除均增加了巨噬细胞核中β-连环蛋白的表达。
巨噬细胞中DKK3的表达通过调节炎症反应和使Wnt/β-连环蛋白通路失活参与动脉粥样硬化的发病机制。
