TY - JOUR
T1 - DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation into Smooth Muscle Cells
AU - Karamariti, Eirini
AU - Zhai, Chungang
AU - Yu, Baoqi
AU - Qiao, Lei
AU - Wang, Zhihong
AU - Potter, Claire M.F.
AU - Wong, Mei Mei
AU - Simpson, Russell M.L.
AU - Zhang, Zhongyi
AU - Wang, Xiaocong
AU - Del Barco Barrantes, Ivan
AU - Niehrs, Christof
AU - Kong, Deling
AU - Zhao, Qiang
AU - Zhang, Yun
AU - Hu, Yanhua
AU - Zhang, Cheng
AU - Xu, Qingbo
PY - 2018/2
Y1 - 2018/2
N2 - 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.
AB - 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.
KW - atherosclerosis E
KW - fibroblasts
KW - phenotype
KW - smooth muscle cells
KW - stem cells
UR - http://www.scopus.com/inward/record.url?scp=85048444436&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.117.310079
DO - 10.1161/ATVBAHA.117.310079
M3 - Article
AN - SCOPUS:85048444436
SN - 1079-5642
VL - 38
SP - 425
EP - 437
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 2
ER -
