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 |
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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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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>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,3688,27929,27930</link.rule.ids><backlink>$$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 & 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 & 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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source | MEDLINE; American Heart Association Journals; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals |
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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