Eirini Karamariti1, Chungang Zhai1, Baoqi Yu1, Lei Qiao1, Zhihong Wang1, Claire M F Potter1, Mei Mei Wong1, Russell M L Simpson1, Zhongyi Zhang1, Xiaocong Wang1, Ivan Del Barco Barrantes1, Christof Niehrs1, Deling Kong1, Qiang Zhao1, Yun Zhang1, Yanhua Hu1, Cheng Zhang2, Qingbo Xu2. 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.
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.
Authors: Ying H Shen; Scott A LeMaire; Nancy R Webb; Lisa A Cassis; Alan Daugherty; Hong S Lu Journal: Arterioscler Thromb Vasc Biol Date: 2020-02-26 Impact factor: 8.311
Authors: Julian C Bachmann; Simon J Baumgart; Anna K Uryga; Markus H Bosteen; Giulia Borghetti; Michael Nyberg; Kate M Herum Journal: Cells Date: 2022-05-17 Impact factor: 7.666
Authors: Ying H Shen; Scott A LeMaire; Nancy R Webb; Lisa A Cassis; Alan Daugherty; Hong S Lu Journal: Arterioscler Thromb Vasc Biol Date: 2020-03-25 Impact factor: 8.311
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2019-12-23 Impact factor: 8.311