LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis

BACKGROUND:Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysre...

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Veröffentlicht in:Circulation (New York, N.Y.) N.Y.), 2019-01, Vol.139 (5), p.679-693
Hauptverfasser: Xie, Yi, Ostriker, Allison C, Jin, Yu, Hu, Haidi, Sizer, Ashley J, Peng, Gang, Morris, Aaron H, Ryu, Changwan, Herzog, Erica L, Kyriakides, Themis, Zhao, Hongyu, Dardik, Alan, Yu, Jun, Hwa, John, Martin, Kathleen A
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container_end_page 693
container_issue 5
container_start_page 679
container_title Circulation (New York, N.Y.)
container_volume 139
creator Xie, Yi
Ostriker, Allison C
Jin, Yu
Hu, Haidi
Sizer, Ashley J
Peng, Gang
Morris, Aaron H
Ryu, Changwan
Herzog, Erica L
Kyriakides, Themis
Zhao, Hongyu
Dardik, Alan
Yu, Jun
Hwa, John
Martin, Kathleen A
description BACKGROUND:Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 & Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown. METHODS:We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle–specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis. RESULTS:We demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1–dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy. CONCLUSIONS:LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.
doi_str_mv 10.1161/CIRCULATIONAHA.118.034615
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The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 &amp; Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown. METHODS:We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle–specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis. RESULTS:We demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1–dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy. CONCLUSIONS:LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/CIRCULATIONAHA.118.034615</identifier><identifier>PMID: 30586711</identifier><language>eng</language><publisher>United States: by the American College of Cardiology Foundation and the American Heart Association, Inc</publisher><subject>Animals ; Cell Proliferation ; Cells, Cultured ; Disease Models, Animal ; Extracellular Matrix - metabolism ; Extracellular Matrix - pathology ; Feedback, Physiological ; Fibrosis ; Hyperplasia ; Integrin alphaVbeta3 - metabolism ; LIM Domain Proteins - deficiency ; LIM Domain Proteins - genetics ; LIM Domain Proteins - metabolism ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle, Smooth, Vascular - injuries ; Muscle, Smooth, Vascular - metabolism ; Muscle, Smooth, Vascular - pathology ; Myocytes, Smooth Muscle - metabolism ; Myocytes, Smooth Muscle - pathology ; Neointima ; Signal Transduction ; Transcription Factor AP-1 - metabolism ; Transcription Factors - deficiency ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transforming Growth Factor beta1 - genetics ; Transforming Growth Factor beta1 - metabolism ; Vascular Remodeling ; Vascular System Injuries - genetics ; Vascular System Injuries - metabolism ; Vascular System Injuries - pathology</subject><ispartof>Circulation (New York, N.Y.), 2019-01, Vol.139 (5), p.679-693</ispartof><rights>2019 by the American College of Cardiology Foundation and the American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3844-9fa78d76b5dad9dc7b0446ab7093d6624525fef352c3fcc2999e7649113383243</citedby><cites>FETCH-LOGICAL-c3844-9fa78d76b5dad9dc7b0446ab7093d6624525fef352c3fcc2999e7649113383243</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,3689,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30586711$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xie, Yi</creatorcontrib><creatorcontrib>Ostriker, Allison C</creatorcontrib><creatorcontrib>Jin, Yu</creatorcontrib><creatorcontrib>Hu, Haidi</creatorcontrib><creatorcontrib>Sizer, Ashley J</creatorcontrib><creatorcontrib>Peng, Gang</creatorcontrib><creatorcontrib>Morris, Aaron H</creatorcontrib><creatorcontrib>Ryu, Changwan</creatorcontrib><creatorcontrib>Herzog, Erica L</creatorcontrib><creatorcontrib>Kyriakides, Themis</creatorcontrib><creatorcontrib>Zhao, Hongyu</creatorcontrib><creatorcontrib>Dardik, Alan</creatorcontrib><creatorcontrib>Yu, Jun</creatorcontrib><creatorcontrib>Hwa, John</creatorcontrib><creatorcontrib>Martin, Kathleen A</creatorcontrib><title>LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>BACKGROUND:Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 &amp; Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown. METHODS:We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle–specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis. RESULTS:We demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1–dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy. CONCLUSIONS:LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.</description><subject>Animals</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Disease Models, Animal</subject><subject>Extracellular Matrix - metabolism</subject><subject>Extracellular Matrix - pathology</subject><subject>Feedback, Physiological</subject><subject>Fibrosis</subject><subject>Hyperplasia</subject><subject>Integrin alphaVbeta3 - metabolism</subject><subject>LIM Domain Proteins - deficiency</subject><subject>LIM Domain Proteins - genetics</subject><subject>LIM Domain Proteins - metabolism</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Muscle, Smooth, Vascular - injuries</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>Neointima</subject><subject>Signal Transduction</subject><subject>Transcription Factor AP-1 - metabolism</subject><subject>Transcription Factors - deficiency</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transforming Growth Factor beta1 - genetics</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><subject>Vascular Remodeling</subject><subject>Vascular System Injuries - genetics</subject><subject>Vascular System Injuries - metabolism</subject><subject>Vascular System Injuries - pathology</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkFtKw0AUhgdRbK1uQcYFpM59Mo8lmLYQW6jto4RJMklj06TMpBa35UJckylRwafD-S_nwAfAA0ZjjAV-DOarYBNN1vPlYjKbdJo_RpQJzC_AEHPCPMapugRDhJDyJCVkAG6ce-tWQSW_BgOKuC8kxkPwGj0vJZw7qOHCFLot3w0MjckSne7gyhTHSreNhU0O11bXLm_svqwLOLXNqd3CUKdn9-sTvpRFrauzpesMhmViG1e6W3CV68qZu585ApvwaR3MvGg5nQeTyEupz5inci39TIqEZzpTWSoTxJjQiUSKZkIQxgnPTU45SWmepkQpZaRgCmNKfUoYHQHV3027t86aPD7Ycq_tR4xRfEYW_0fWaX7cI-u69333cEz2Jvtr_jLqAqwPnJqqNdbtquPJ2HhrdNVu4w4qoghLjyCsECYKeZ2CGf0GjqR4ag</recordid><startdate>20190129</startdate><enddate>20190129</enddate><creator>Xie, Yi</creator><creator>Ostriker, Allison C</creator><creator>Jin, Yu</creator><creator>Hu, Haidi</creator><creator>Sizer, Ashley J</creator><creator>Peng, Gang</creator><creator>Morris, Aaron H</creator><creator>Ryu, Changwan</creator><creator>Herzog, Erica L</creator><creator>Kyriakides, Themis</creator><creator>Zhao, Hongyu</creator><creator>Dardik, Alan</creator><creator>Yu, Jun</creator><creator>Hwa, John</creator><creator>Martin, Kathleen A</creator><general>by the American College of Cardiology Foundation and the 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></search><sort><creationdate>20190129</creationdate><title>LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis</title><author>Xie, Yi ; Ostriker, Allison C ; Jin, Yu ; Hu, Haidi ; Sizer, Ashley J ; Peng, Gang ; Morris, Aaron H ; Ryu, Changwan ; Herzog, Erica L ; Kyriakides, Themis ; Zhao, Hongyu ; Dardik, Alan ; Yu, Jun ; Hwa, John ; Martin, Kathleen A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3844-9fa78d76b5dad9dc7b0446ab7093d6624525fef352c3fcc2999e7649113383243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Disease Models, Animal</topic><topic>Extracellular Matrix - metabolism</topic><topic>Extracellular Matrix - pathology</topic><topic>Feedback, Physiological</topic><topic>Fibrosis</topic><topic>Hyperplasia</topic><topic>Integrin alphaVbeta3 - metabolism</topic><topic>LIM Domain Proteins - deficiency</topic><topic>LIM Domain Proteins - genetics</topic><topic>LIM Domain Proteins - metabolism</topic><topic>Male</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Muscle, Smooth, Vascular - injuries</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>Neointima</topic><topic>Signal Transduction</topic><topic>Transcription Factor AP-1 - metabolism</topic><topic>Transcription Factors - deficiency</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transforming Growth Factor beta1 - genetics</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><topic>Vascular Remodeling</topic><topic>Vascular System Injuries - genetics</topic><topic>Vascular System Injuries - metabolism</topic><topic>Vascular System Injuries - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xie, Yi</creatorcontrib><creatorcontrib>Ostriker, Allison C</creatorcontrib><creatorcontrib>Jin, Yu</creatorcontrib><creatorcontrib>Hu, Haidi</creatorcontrib><creatorcontrib>Sizer, Ashley J</creatorcontrib><creatorcontrib>Peng, Gang</creatorcontrib><creatorcontrib>Morris, Aaron H</creatorcontrib><creatorcontrib>Ryu, Changwan</creatorcontrib><creatorcontrib>Herzog, Erica L</creatorcontrib><creatorcontrib>Kyriakides, Themis</creatorcontrib><creatorcontrib>Zhao, Hongyu</creatorcontrib><creatorcontrib>Dardik, Alan</creatorcontrib><creatorcontrib>Yu, Jun</creatorcontrib><creatorcontrib>Hwa, John</creatorcontrib><creatorcontrib>Martin, Kathleen A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xie, Yi</au><au>Ostriker, Allison C</au><au>Jin, Yu</au><au>Hu, Haidi</au><au>Sizer, Ashley J</au><au>Peng, Gang</au><au>Morris, Aaron H</au><au>Ryu, Changwan</au><au>Herzog, Erica L</au><au>Kyriakides, Themis</au><au>Zhao, Hongyu</au><au>Dardik, Alan</au><au>Yu, Jun</au><au>Hwa, John</au><au>Martin, Kathleen A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2019-01-29</date><risdate>2019</risdate><volume>139</volume><issue>5</issue><spage>679</spage><epage>693</epage><pages>679-693</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><abstract>BACKGROUND:Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 &amp; Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown. METHODS:We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle–specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis. RESULTS:We demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1–dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy. CONCLUSIONS:LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.</abstract><cop>United States</cop><pub>by the American College of Cardiology Foundation and the American Heart Association, Inc</pub><pmid>30586711</pmid><doi>10.1161/CIRCULATIONAHA.118.034615</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record>
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subjects Animals
Cell Proliferation
Cells, Cultured
Disease Models, Animal
Extracellular Matrix - metabolism
Extracellular Matrix - pathology
Feedback, Physiological
Fibrosis
Hyperplasia
Integrin alphaVbeta3 - metabolism
LIM Domain Proteins - deficiency
LIM Domain Proteins - genetics
LIM Domain Proteins - metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular - injuries
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
Myocytes, Smooth Muscle - metabolism
Myocytes, Smooth Muscle - pathology
Neointima
Signal Transduction
Transcription Factor AP-1 - metabolism
Transcription Factors - deficiency
Transcription Factors - genetics
Transcription Factors - metabolism
Transforming Growth Factor beta1 - genetics
Transforming Growth Factor beta1 - metabolism
Vascular Remodeling
Vascular System Injuries - genetics
Vascular System Injuries - metabolism
Vascular System Injuries - pathology
title LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis
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