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Arterioscler Thromb Vasc Biol. 2018 Feb;38(2):425-437. doi: 10.1161/ATVBAHA.117.310079. Epub 2017 Dec 28.

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

Author information

1
From the School of Cardiovascular Medicine & Sciences, King's College London BHF Centre, United Kingdom (E.K., B.Y., C.M.F.P., M.M.W., R.M.L.S., Z.Z., X.W., Y.H., Q.X.); The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, China (C. Zhai, L.Q., Y.Z., C. Zhang); State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China (Z.W., D.K., Q.Z.); Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Germany (I.d.B.B., C.N.); and Institute of Molecular Biology (IMB), Mainz, Germany (C.N.).
2
From the School of Cardiovascular Medicine & Sciences, King's College London BHF Centre, United Kingdom (E.K., B.Y., C.M.F.P., M.M.W., R.M.L.S., Z.Z., X.W., Y.H., Q.X.); The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, China (C. Zhai, L.Q., Y.Z., C. Zhang); State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China (Z.W., D.K., Q.Z.); Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Germany (I.d.B.B., C.N.); and Institute of Molecular Biology (IMB), Mainz, Germany (C.N.). qingbo.xu@kcl.ac.uk zhangc@sdu.edu.cn.

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.

KEYWORDS:

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

PMID:
29284609
DOI:
10.1161/ATVBAHA.117.310079
[Indexed for MEDLINE]

Publication type, MeSH terms, Substances, Grant support

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