DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells
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 effect...
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| Veröffentlicht in: | Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2018-02, Vol.38 (2), p.425-437 |
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| creator | Karamariti, Eirini Zhai, Chungang Yu, Baoqi Qiao, Lei Wang, Zhihong Potter, Claire M.F Wong, Mei Mei Simpson, Russell M.L Zhang, Zhongyi Wang, Xiaocong del Barco Barrantes, Ivan Niehrs, Christof Kong, Deling Zhao, Qiang Zhang, Yun Hu, Yanhua Zhang, Cheng Xu, Qingbo |
| description | 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. |
| doi_str_mv | 10.1161/ATVBAHA.117.310079 |
| format | Article |
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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.</description><identifier>ISSN: 1079-5642</identifier><identifier>EISSN: 1524-4636</identifier><identifier>DOI: 10.1161/ATVBAHA.117.310079</identifier><identifier>PMID: 29284609</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Activating Transcription Factor 6 - genetics ; Activating Transcription Factor 6 - metabolism ; Adaptor Proteins, Signal Transducing ; Animals ; Aorta - metabolism ; Aorta - pathology ; Aortic Diseases - genetics ; Aortic Diseases - metabolism ; Aortic Diseases - pathology ; Ataxin-1 - metabolism ; Atherosclerosis - genetics ; Atherosclerosis - metabolism ; Atherosclerosis - pathology ; Carotid Arteries - metabolism ; Carotid Arteries - pathology ; Carotid Stenosis - genetics ; Carotid Stenosis - metabolism ; Carotid Stenosis - pathology ; Cell Transdifferentiation ; Cells, Cultured ; Chemokines ; Disease Models, Animal ; Female ; Fibroblasts - metabolism ; Fibroblasts - pathology ; Hemorrhage - genetics ; Hemorrhage - metabolism ; Hemorrhage - pathology ; Hemorrhage - prevention & control ; Humans ; Intercellular Signaling Peptides and Proteins - deficiency ; Intercellular Signaling Peptides and Proteins - genetics ; Intercellular Signaling Peptides and Proteins - metabolism ; Male ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; Muscle, Smooth, Vascular - metabolism ; Muscle, Smooth, Vascular - pathology ; Myocytes, Smooth Muscle - metabolism ; Myocytes, Smooth Muscle - pathology ; Phenotype ; Plaque, Atherosclerotic ; Rabbits ; Stem Cells - metabolism ; Stem Cells - pathology ; Transforming Growth Factor beta1 - metabolism ; Wnt Signaling Pathway</subject><ispartof>Arteriosclerosis, thrombosis, and vascular biology, 2018-02, Vol.38 (2), p.425-437</ispartof><rights>2018 American Heart Association, Inc.</rights><rights>2017 The Authors.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4439-13a9955abc84aaf25b73592801c8b26a3a3c373becce5e474ce47374c464d1003</citedby><cites>FETCH-LOGICAL-c4439-13a9955abc84aaf25b73592801c8b26a3a3c373becce5e474ce47374c464d1003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29284609$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Karamariti, Eirini</creatorcontrib><creatorcontrib>Zhai, Chungang</creatorcontrib><creatorcontrib>Yu, Baoqi</creatorcontrib><creatorcontrib>Qiao, Lei</creatorcontrib><creatorcontrib>Wang, Zhihong</creatorcontrib><creatorcontrib>Potter, Claire M.F</creatorcontrib><creatorcontrib>Wong, Mei Mei</creatorcontrib><creatorcontrib>Simpson, Russell M.L</creatorcontrib><creatorcontrib>Zhang, Zhongyi</creatorcontrib><creatorcontrib>Wang, Xiaocong</creatorcontrib><creatorcontrib>del Barco Barrantes, Ivan</creatorcontrib><creatorcontrib>Niehrs, Christof</creatorcontrib><creatorcontrib>Kong, Deling</creatorcontrib><creatorcontrib>Zhao, Qiang</creatorcontrib><creatorcontrib>Zhang, Yun</creatorcontrib><creatorcontrib>Hu, Yanhua</creatorcontrib><creatorcontrib>Zhang, Cheng</creatorcontrib><creatorcontrib>Xu, Qingbo</creatorcontrib><title>DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells</title><title>Arteriosclerosis, thrombosis, and vascular biology</title><addtitle>Arterioscler Thromb Vasc Biol</addtitle><description>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.</description><subject>Activating Transcription Factor 6 - genetics</subject><subject>Activating Transcription Factor 6 - metabolism</subject><subject>Adaptor Proteins, Signal Transducing</subject><subject>Animals</subject><subject>Aorta - metabolism</subject><subject>Aorta - pathology</subject><subject>Aortic Diseases - genetics</subject><subject>Aortic Diseases - metabolism</subject><subject>Aortic Diseases - pathology</subject><subject>Ataxin-1 - metabolism</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - metabolism</subject><subject>Atherosclerosis - pathology</subject><subject>Carotid Arteries - metabolism</subject><subject>Carotid Arteries - pathology</subject><subject>Carotid Stenosis - genetics</subject><subject>Carotid Stenosis - metabolism</subject><subject>Carotid Stenosis - pathology</subject><subject>Cell Transdifferentiation</subject><subject>Cells, Cultured</subject><subject>Chemokines</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - pathology</subject><subject>Hemorrhage - genetics</subject><subject>Hemorrhage - metabolism</subject><subject>Hemorrhage - pathology</subject><subject>Hemorrhage - prevention & control</subject><subject>Humans</subject><subject>Intercellular Signaling Peptides and Proteins - deficiency</subject><subject>Intercellular Signaling Peptides and Proteins - genetics</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout, ApoE</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Muscle, Smooth, Vascular - pathology</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Myocytes, Smooth Muscle - pathology</subject><subject>Phenotype</subject><subject>Plaque, Atherosclerotic</subject><subject>Rabbits</subject><subject>Stem Cells - metabolism</subject><subject>Stem Cells - pathology</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><subject>Wnt Signaling Pathway</subject><issn>1079-5642</issn><issn>1524-4636</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UctOHDEQtBAREJIfyAH5SA5D_JrXcdgNAUGUlUK4jjzeHsasd7yxPSC-Ir9Mw25yzKXbbVWV3VWEfOLsjPOCf2lu786bywaH8kxyxsp6jxzxXKhMFbLYxzNeZXmhxCF5H-MDY0wJwQ7IoahFpQpWH5E_8-trSU_n1qxWftNT-Zk2LkGItEkDBB-Nw5qsoQunf09AFwOMPj1vgF6Nj9492vGe3uloJqcDXQR_D6NNPlA9LumF7YLvnI6Jzm3fQ4AxWZ2sH5GcPP259j4N9Pv0-gqdgXPxA3nXaxfh464fk18XX29nl9nNj29Xs-YmM0rJOuNS13We685USute5F0pc1yKcVN1otBSSyNL2YExkIMqlcEisalCLdEqeUxOt7qb4HGtmNq1jQZ_oEfwU2x5XaFFUqoKoWILNWhHDNC3m2DXOjy3nLWvQbS7IHAo220QSDrZ6U_dGpb_KH-dR0CxBTz5N79XbnqC0A6gXRr-p_wC1XiWoA</recordid><startdate>201802</startdate><enddate>201802</enddate><creator>Karamariti, Eirini</creator><creator>Zhai, Chungang</creator><creator>Yu, Baoqi</creator><creator>Qiao, Lei</creator><creator>Wang, Zhihong</creator><creator>Potter, Claire M.F</creator><creator>Wong, Mei Mei</creator><creator>Simpson, Russell M.L</creator><creator>Zhang, Zhongyi</creator><creator>Wang, Xiaocong</creator><creator>del Barco Barrantes, Ivan</creator><creator>Niehrs, Christof</creator><creator>Kong, Deling</creator><creator>Zhao, Qiang</creator><creator>Zhang, Yun</creator><creator>Hu, Yanhua</creator><creator>Zhang, Cheng</creator><creator>Xu, Qingbo</creator><general>American Heart Association, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201802</creationdate><title>DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells</title><author>Karamariti, Eirini ; Zhai, Chungang ; Yu, Baoqi ; Qiao, Lei ; Wang, Zhihong ; Potter, Claire M.F ; Wong, Mei Mei ; Simpson, Russell M.L ; Zhang, Zhongyi ; Wang, Xiaocong ; del Barco Barrantes, Ivan ; Niehrs, Christof ; Kong, Deling ; Zhao, Qiang ; Zhang, Yun ; Hu, Yanhua ; Zhang, Cheng ; Xu, Qingbo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4439-13a9955abc84aaf25b73592801c8b26a3a3c373becce5e474ce47374c464d1003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Activating Transcription Factor 6 - genetics</topic><topic>Activating Transcription Factor 6 - metabolism</topic><topic>Adaptor Proteins, Signal Transducing</topic><topic>Animals</topic><topic>Aorta - metabolism</topic><topic>Aorta - pathology</topic><topic>Aortic Diseases - genetics</topic><topic>Aortic Diseases - metabolism</topic><topic>Aortic Diseases - pathology</topic><topic>Ataxin-1 - metabolism</topic><topic>Atherosclerosis - genetics</topic><topic>Atherosclerosis - metabolism</topic><topic>Atherosclerosis - pathology</topic><topic>Carotid Arteries - metabolism</topic><topic>Carotid Arteries - pathology</topic><topic>Carotid Stenosis - genetics</topic><topic>Carotid Stenosis - metabolism</topic><topic>Carotid Stenosis - pathology</topic><topic>Cell Transdifferentiation</topic><topic>Cells, Cultured</topic><topic>Chemokines</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Fibroblasts - metabolism</topic><topic>Fibroblasts - pathology</topic><topic>Hemorrhage - genetics</topic><topic>Hemorrhage - metabolism</topic><topic>Hemorrhage - pathology</topic><topic>Hemorrhage - prevention & control</topic><topic>Humans</topic><topic>Intercellular Signaling Peptides and Proteins - deficiency</topic><topic>Intercellular Signaling Peptides and Proteins - genetics</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Male</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout, ApoE</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Muscle, Smooth, Vascular - pathology</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Myocytes, Smooth Muscle - pathology</topic><topic>Phenotype</topic><topic>Plaque, Atherosclerotic</topic><topic>Rabbits</topic><topic>Stem Cells - metabolism</topic><topic>Stem Cells - pathology</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><topic>Wnt Signaling Pathway</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Karamariti, Eirini</creatorcontrib><creatorcontrib>Zhai, Chungang</creatorcontrib><creatorcontrib>Yu, Baoqi</creatorcontrib><creatorcontrib>Qiao, Lei</creatorcontrib><creatorcontrib>Wang, Zhihong</creatorcontrib><creatorcontrib>Potter, Claire M.F</creatorcontrib><creatorcontrib>Wong, Mei Mei</creatorcontrib><creatorcontrib>Simpson, Russell M.L</creatorcontrib><creatorcontrib>Zhang, Zhongyi</creatorcontrib><creatorcontrib>Wang, Xiaocong</creatorcontrib><creatorcontrib>del Barco Barrantes, Ivan</creatorcontrib><creatorcontrib>Niehrs, Christof</creatorcontrib><creatorcontrib>Kong, Deling</creatorcontrib><creatorcontrib>Zhao, Qiang</creatorcontrib><creatorcontrib>Zhang, Yun</creatorcontrib><creatorcontrib>Hu, Yanhua</creatorcontrib><creatorcontrib>Zhang, Cheng</creatorcontrib><creatorcontrib>Xu, Qingbo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Karamariti, Eirini</au><au>Zhai, Chungang</au><au>Yu, Baoqi</au><au>Qiao, Lei</au><au>Wang, Zhihong</au><au>Potter, Claire M.F</au><au>Wong, Mei Mei</au><au>Simpson, Russell M.L</au><au>Zhang, Zhongyi</au><au>Wang, Xiaocong</au><au>del Barco Barrantes, Ivan</au><au>Niehrs, Christof</au><au>Kong, Deling</au><au>Zhao, Qiang</au><au>Zhang, Yun</au><au>Hu, Yanhua</au><au>Zhang, Cheng</au><au>Xu, Qingbo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells</atitle><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle><addtitle>Arterioscler Thromb Vasc Biol</addtitle><date>2018-02</date><risdate>2018</risdate><volume>38</volume><issue>2</issue><spage>425</spage><epage>437</epage><pages>425-437</pages><issn>1079-5642</issn><eissn>1524-4636</eissn><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.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>29284609</pmid><doi>10.1161/ATVBAHA.117.310079</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Arteriosclerosis, thrombosis, and vascular biology, 2018-02, Vol.38 (2), p.425-437 |
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| source | MEDLINE; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Activating Transcription Factor 6 - genetics Activating Transcription Factor 6 - metabolism Adaptor Proteins, Signal Transducing Animals Aorta - metabolism Aorta - pathology Aortic Diseases - genetics Aortic Diseases - metabolism Aortic Diseases - pathology Ataxin-1 - metabolism Atherosclerosis - genetics Atherosclerosis - metabolism Atherosclerosis - pathology Carotid Arteries - metabolism Carotid Arteries - pathology Carotid Stenosis - genetics Carotid Stenosis - metabolism Carotid Stenosis - pathology Cell Transdifferentiation Cells, Cultured Chemokines Disease Models, Animal Female Fibroblasts - metabolism Fibroblasts - pathology Hemorrhage - genetics Hemorrhage - metabolism Hemorrhage - pathology Hemorrhage - prevention & control Humans Intercellular Signaling Peptides and Proteins - deficiency Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Male Mice, Inbred C57BL Mice, Knockout, ApoE Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Phenotype Plaque, Atherosclerotic Rabbits Stem Cells - metabolism Stem Cells - pathology Transforming Growth Factor beta1 - metabolism Wnt Signaling Pathway |
| title | DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells |
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