Dickkopf‐3 Ablation Attenuates the Development of Atherosclerosis in ApoE‐Deficient Mice

• Published in: Journal of the American Heart Association Vol. 6; no. 2
• Main Authors: Cheng, Wen‐Lin, Yang, Yang, Zhang, Xiao‐Jing, Guo, Junhong, Gong, Jun, Gong, Fu‐Han, She, Zhi‐Gang, Huang, Zan, Xia, Hao, Li, Hongliang
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 20.02.2017; Wiley
• Subjects: Adult; Aged; Animals; Apolipoproteins E - deficiency; atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; beta Catenin - biosynthesis; beta Catenin - genetics; Blotting, Western; Coronary Artery Disease - genetics; Coronary Artery Disease - metabolism; Coronary Artery Disease - pathology; dickkopf‐3; Disease Models, Animal; Female; Gene Expression Regulation; Humans; inflammation; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; macrophage; Macrophages - metabolism; Macrophages - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Original Research; Real-Time Polymerase Chain Reaction; RNA, Messenger - genetics; β‐catenin; atherosclerosis; dickkopf‐3; macrophage; β‐catenin; inflammation
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.116.004690

Background 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. Methods and Results 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. DKK3−/−ApoE−/− mice exhibited a significant decrease in atherosclerotic lesions in the entire aorta, aortic sinus, and brachiocephalic arteries. Transplantation of bone marrow from DKK3−/−ApoE−/− 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 DKK3−/−ApoE−/− mice. Furthermore, multiple proinflammatory cytokines exhibited marked decreases in DKK3−/−ApoE−/− mice. Finally, we observed that DKK3 ablation increased β‐catenin expression in the nuclei of macrophages both in vivo and in vitro. Conclusions DKK3 expression in macrophages is involved in the pathogenesis of atherosclerosis through modulation of inflammation and inactivation of the Wnt/β‐catenin pathway.