DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation into Smooth Muscle Cells

Eirini Karamariti, Chungang Zhai, Baoqi Yu, Lei Qiao, Zhihong Wang, Claire M.F. Potter, Mei Mei Wong, Russell M.L. Simpson, Zhongyi Zhang, Xiaocong Wang, Ivan Del Barco Barrantes, Christof Niehrs, Deling Kong, Qiang Zhao, Yun Zhang, Yanhua Hu, Cheng Zhang, Qingbo Xu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

Objective-DKK3 (dickkopf 3), a 36-kD secreted glycoprotein, has been shown to be involved in the differentiation of partially reprogrammed cells and embryonic stem cells to smooth muscle cells (SMCs), but little is known about its involvement in vascular disease. This study aims to assess the effects of DKK3 on atherosclerotic plaque composition. Approach and Results-In the present study, we used a murine model of atherosclerosis (ApoE-/-) in conjunction with DKK3-/- and performed tandem stenosis of the carotid artery to evaluate atherosclerotic plaque development. We found that the absence of DKK3 leads to vulnerable atherosclerotic plaques, because of a reduced number of SMCs and reduced matrix protein deposition, as well as increased hemorrhage and macrophage infiltration. Further in vitro studies revealed that DKK3 can induce differentiation of Sca1+ (stem cells antigen 1) vascular progenitors and fibroblasts into SMCs via activation of the TGF-β (transforming growth factor-β)/ATF6 (activating transcription factor 6) and Wnt signaling pathways. Finally, we assessed the therapeutic potential of DKK3 in mouse and rabbit models and found that DKK3 altered the atherosclerotic plaque content via increasing SMC numbers and reducing vascular inflammation. Conclusions-Cumulatively, we provide the first evidence that DKK3 is a potent SMC differentiation factor, which might have a therapeutic effect in reducing intraplaque hemorrhage related to atherosclerotic plaque phenotype.

Original languageEnglish
Pages (from-to)425-437
Number of pages13
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume38
Issue number2
Early online date28 Dec 2017
DOIs
Publication statusPublished - Feb 2018

Keywords

  • atherosclerosis E
  • fibroblasts
  • phenotype
  • smooth muscle cells
  • stem cells

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