title: Dickkopf-3 Ablation Attenuates the Development of Atherosclerosis in ApoE-Deficient Mice.
abstract: 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. 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.
  
  
  
  DKK3 expression in macrophages is involved in the pathogenesis of atherosclerosis through modulation of inflammation and inactivation of the Wnt/β-catenin pathway.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|The Institute of Model Animals of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|The Institute of Model Animals of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|The Institute of Model Animals of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Junhong
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|The Institute of Model Animals of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Fu-Han
authors.initials: FH
authors.lastname: Gong
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|The Institute of Model Animals of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: She
authors.affiliation: College of Life Science, Wuhan University, Wuhan, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China lihl@whu.edu.cn xiahao1966@163.com.|Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China lihl@whu.edu.cn xiahao1966@163.com.|The Institute of Model Animals of Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; C405061:Dkk3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D051176:beta Catenin
keywords: atherosclerosis; dickkopf‐3; inflammation; macrophage; β‐catenin