PMID- 34030936
OWN - NLM
STAT- MEDLINE
DCOM- 20211124
LR  - 20220531
IS  - 1876-4738 (Electronic)
IS  - 0914-5087 (Linking)
VI  - 78
IP  - 4
DP  - 2021 Oct
TI  - Dickkopf-2 knockdown protects against classic macrophage polarization and lipid 
      loading by activation of Wnt/beta-catenin signaling.
PG  - 328-333
LID - S0914-5087(21)00107-6 [pii]
LID - 10.1016/j.jjcc.2021.04.010 [doi]
AB  - OBJECTIVES: Wnt/beta-catenin signaling pathway plays an important role in regulation 
      of macrophage activation implicated in the development of atherosclerosis. 
      However, as a negative regulator of Wnt/beta-catenin, the potential role of 
      Dickkopf-2 (Dkk2) on macrophage activation remains unexplored. MATERIALS AND 
      METHODS: Bone marrow-derived macrophages (BMDMs) and mouse peritoneal macrophages 
      (MPMs) collected from ApoE knockout mice upon oxidation low lipoprotein (Ox-LDL) 
      administration were performed to test the expression of Dkk2. The 
      loss-of-function strategy using siRNA-Dkk2 was further utilized for the function 
      of Dkk2. Inhibition of beta-catenin with XAV939 (a beta-catenin specific inhibitor) was 
      further used for testing its effect on macrophage activation mediated by Dkk2 
      knockdown. RESULTS AND CONCLUSION: In the current study, real time-polymerase 
      chain reaction analysis demonstrated that an up-regulated Dkk2 expression was 
      observed in BMDMs and MPMs of ApoE knockout mice upon Ox-LDL administration, 
      which was confirmed by western blot. The double immunofluorescence staining 
      further exhibited that Dkk2 showed a strong immunoreactivity in BMDMs and 
      primarily located in cytoplasm of macrophages. Dkk2 knockdown significantly 
      decreased the genes related to classic M1 polarized macrophage but increased 
      alternative M2 polarized macrophage markers. Moreover, Dkk2 silencing 
      dramatically attenuated foam cell formation which was contributed by promoted 
      markers' expression associated with cholesterol efflux but attenuated markers to 
      cholesterol influx. Mechanistically, we observed that Dkk2 knockdown activated 
      Wnt/beta-catenin signaling by promoting beta-catenin to translocate into the nuclei of 
      macrophages, and XAV939 reversed the ameliorated effect of Dkk2 silencing 
      macrophage activation. Taken together, these results suggested that downregulated 
      Dkk2 expression in macrophages was responsible for the inactivation of macrophage 
      through targeting Wnt/beta-catenin pathway.
CI  - Copyright (c) 2021. Published by Elsevier Ltd.
FAU - Zhang, Yuan
AU  - Zhang Y
AD  - Center of Cardiology, Chong Qing General Hospital, University of Chinese Academy 
      of Sciences, Chongqing, PR China.
FAU - Wu, Hongkun
AU  - Wu H
AD  - Center of Cardiology, Chong Qing General Hospital, University of Chinese Academy 
      of Sciences, Chongqing, PR China.
FAU - He, Rui
AU  - He R
AD  - Center of Cardiology, Chong Qing General Hospital, University of Chinese Academy 
      of Sciences, Chongqing, PR China.
FAU - Ye, Changlun
AU  - Ye C
AD  - Department of Cardiology, Chongqing Qijiang District People's Hospital, 
      Chongqing, PR China.
FAU - Chen, Hao
AU  - Chen H
AD  - Center of Cardiology, Chong Qing General Hospital, University of Chinese Academy 
      of Sciences, Chongqing, PR China.
FAU - Wang, Jiao
AU  - Wang J
AD  - Center of Cardiology, Chong Qing General Hospital, University of Chinese Academy 
      of Sciences, Chongqing, PR China.
FAU - Li, Zhenggong
AU  - Li Z
AD  - Center of Cardiology, Chong Qing General Hospital, University of Chinese Academy 
      of Sciences, Chongqing, PR China. Electronic address: li_zheng_gong_cq@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210522
PL  - Netherlands
TA  - J Cardiol
JT  - Journal of cardiology
JID - 8804703
RN  - 0 (Dkk2 protein, mouse)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lipids)
RN  - 0 (beta Catenin)
SB  - IM
MH  - Animals
MH  - Intercellular Signaling Peptides and Proteins/genetics/*metabolism
MH  - Lipids
MH  - *Macrophage Activation
MH  - Macrophages/metabolism
MH  - Mice
MH  - *Wnt Signaling Pathway
MH  - beta Catenin/metabolism
OTO - NOTNLM
OT  - Atherosclerosis
OT  - Dickkopf-2
OT  - Macrophage polarization
OT  - Wnt/ beta-catenin
COIS- Declaration of competing interest None.
EDAT- 2021/05/26 06:00
MHDA- 2021/11/25 06:00
CRDT- 2021/05/25 06:00
PHST- 2021/01/25 00:00 [received]
PHST- 2021/04/13 00:00 [revised]
PHST- 2021/04/16 00:00 [accepted]
PHST- 2021/05/26 06:00 [pubmed]
PHST- 2021/11/25 06:00 [medline]
PHST- 2021/05/25 06:00 [entrez]
AID - S0914-5087(21)00107-6 [pii]
AID - 10.1016/j.jjcc.2021.04.010 [doi]
PST - ppublish
SO  - J Cardiol. 2021 Oct;78(4):328-333. doi: 10.1016/j.jjcc.2021.04.010. Epub 2021 May 
      22.