MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis
Identifieur interne : 000A02 ( Istex/Corpus ); précédent : 000A01; suivant : 000A03MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis
Auteurs : Helen Williams ; Jason L. Johnson ; Christopher L. Jackson ; Stephen J. White ; Sarah J. GeorgeSource :
- Cardiovascular Research [ 0008-6363 ] ; 2010-07-01.
Abstract
Aims Vascular smooth muscle cell (VSMC) apoptosis can lead to thinning of the fibrous cap and plaque instability. We previously showed that cellcell contacts mediated by N-cadherin reduce VSMC apoptosis. This study aimed to determine whether matrix-degrading metalloproteinase (MMP)-dependent N-cadherin cleavage causes VSMC apoptosis. Methods and results Induction of human VSMC apoptosis using different approaches, including 200 ng/mL Fas ligand (Fas-L) and culture in suspension, caused N-cadherin cleavage and resulted in the appearance of a C-terminal fragment of N-cadherin (35 kDa). Appearance of this fragment during apoptosis was inhibited by 47 with the broad-spectrum MMP inhibitor BB-94. We observed retarded cleavage of N-cadherin after treatment with Fas-L in aortic mouse VSMCs lacking MMP-7. Furthermore, VSMC apoptosis, measured by quantification of cleaved caspase-3, was 43 lower in MMP-7 knockout mouse VSMCs compared with wild-type VSMCs following treatment with Fas-L. Addition of recombinant active MMP-7 increased the amount of N-cadherin fragment by 82 and augmented apoptosis by 53. The involvement of MMP-7 was corroborated using human cells, where a MMP-7 selective inhibitor reduced the amount of fragment formed by 51. Importantly, we observed that treatment with Fas-L increased levels of active MMP-7 by 80. Finally, we observed significantly increased cleavage of N-cadherin, MMP-7 activity, and apoptosis in human atherosclerotic plaques compared with control arteries, and a significant reduction in apoptosis in atherosclerotic plaques from MMP-7 knockout mice. Conclusion This study demonstrates that MMP-7 is involved in the cleavage of N-cadherin and modulates VSMC apoptosis, and may therefore contribute to plaque development and rupture.
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DOI: 10.1093/cvr/cvq042
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Johnson</name><affiliation><mods:affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</mods:affiliation></affiliation></author><author><name sortKey="Jackson, Christopher L" sort="Jackson, Christopher L" uniqKey="Jackson C" first="Christopher L." last="Jackson">Christopher L. Jackson</name><affiliation><mods:affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</mods:affiliation></affiliation></author><author><name sortKey="White, Stephen J" sort="White, Stephen J" uniqKey="White S" first="Stephen J." last="White">Stephen J. White</name><affiliation><mods:affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</mods:affiliation></affiliation></author><author><name sortKey="George, Sarah J" sort="George, Sarah J" uniqKey="George S" first="Sarah J." last="George">Sarah J. George</name><affiliation><mods:affiliation>E-mail: s.j.george@bris.ac.uk</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1093/cvr/cvq042</idno><idno type="url">https://api.istex.fr/document/650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000A02</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis</title><author><name sortKey="Williams, Helen" sort="Williams, Helen" uniqKey="Williams H" first="Helen" last="Williams">Helen Williams</name><affiliation><mods:affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</mods:affiliation></affiliation></author><author><name sortKey="Johnson, Jason L" sort="Johnson, Jason L" uniqKey="Johnson J" first="Jason L." last="Johnson">Jason L. Johnson</name><affiliation><mods:affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</mods:affiliation></affiliation></author><author><name sortKey="Jackson, Christopher L" sort="Jackson, Christopher L" uniqKey="Jackson C" first="Christopher L." last="Jackson">Christopher L. Jackson</name><affiliation><mods:affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</mods:affiliation></affiliation></author><author><name sortKey="White, Stephen J" sort="White, Stephen J" uniqKey="White S" first="Stephen J." last="White">Stephen J. White</name><affiliation><mods:affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</mods:affiliation></affiliation></author><author><name sortKey="George, Sarah J" sort="George, Sarah J" uniqKey="George S" first="Sarah J." last="George">Sarah J. George</name><affiliation><mods:affiliation>E-mail: s.j.george@bris.ac.uk</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Cardiovascular Research</title><idno type="ISSN">0008-6363</idno><idno type="eISSN">1755-3245</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-07-01">2010-07-01</date><biblScope unit="volume">87</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="137">137</biblScope><biblScope unit="page" to="146">146</biblScope></imprint><idno type="ISSN">0008-6363</idno></series><idno type="istex">650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9</idno><idno type="DOI">10.1093/cvr/cvq042</idno><idno type="ArticleID">cvq042</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0008-6363</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Aims Vascular smooth muscle cell (VSMC) apoptosis can lead to thinning of the fibrous cap and plaque instability. We previously showed that cellcell contacts mediated by N-cadherin reduce VSMC apoptosis. This study aimed to determine whether matrix-degrading metalloproteinase (MMP)-dependent N-cadherin cleavage causes VSMC apoptosis. Methods and results Induction of human VSMC apoptosis using different approaches, including 200 ng/mL Fas ligand (Fas-L) and culture in suspension, caused N-cadherin cleavage and resulted in the appearance of a C-terminal fragment of N-cadherin (35 kDa). Appearance of this fragment during apoptosis was inhibited by 47 with the broad-spectrum MMP inhibitor BB-94. We observed retarded cleavage of N-cadherin after treatment with Fas-L in aortic mouse VSMCs lacking MMP-7. Furthermore, VSMC apoptosis, measured by quantification of cleaved caspase-3, was 43 lower in MMP-7 knockout mouse VSMCs compared with wild-type VSMCs following treatment with Fas-L. Addition of recombinant active MMP-7 increased the amount of N-cadherin fragment by 82 and augmented apoptosis by 53. The involvement of MMP-7 was corroborated using human cells, where a MMP-7 selective inhibitor reduced the amount of fragment formed by 51. Importantly, we observed that treatment with Fas-L increased levels of active MMP-7 by 80. Finally, we observed significantly increased cleavage of N-cadherin, MMP-7 activity, and apoptosis in human atherosclerotic plaques compared with control arteries, and a significant reduction in apoptosis in atherosclerotic plaques from MMP-7 knockout mice. Conclusion This study demonstrates that MMP-7 is involved in the cleavage of N-cadherin and modulates VSMC apoptosis, and may therefore contribute to plaque development and rupture.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Helen Williams</name><affiliations><json:string>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</json:string></affiliations></json:item><json:item><name>Jason L. Johnson</name><affiliations><json:string>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</json:string></affiliations></json:item><json:item><name>Christopher L. Jackson</name><affiliations><json:string>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</json:string></affiliations></json:item><json:item><name>Stephen J. White</name><affiliations><json:string>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</json:string></affiliations></json:item><json:item><name>Sarah J. George</name><affiliations><json:string>E-mail: s.j.george@bris.ac.uk</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Vascular smooth muscle</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Apoptosis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Atherosclerosis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Matrix-degrading metalloproteinase-7</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>N-cadherin</value></json:item></subject><articleId><json:string>cvq042</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Aims Vascular smooth muscle cell (VSMC) apoptosis can lead to thinning of the fibrous cap and plaque instability. We previously showed that cellcell contacts mediated by N-cadherin reduce VSMC apoptosis. This study aimed to determine whether matrix-degrading metalloproteinase (MMP)-dependent N-cadherin cleavage causes VSMC apoptosis. Methods and results Induction of human VSMC apoptosis using different approaches, including 200 ng/mL Fas ligand (Fas-L) and culture in suspension, caused N-cadherin cleavage and resulted in the appearance of a C-terminal fragment of N-cadherin (35 kDa). Appearance of this fragment during apoptosis was inhibited by 47 with the broad-spectrum MMP inhibitor BB-94. We observed retarded cleavage of N-cadherin after treatment with Fas-L in aortic mouse VSMCs lacking MMP-7. Furthermore, VSMC apoptosis, measured by quantification of cleaved caspase-3, was 43 lower in MMP-7 knockout mouse VSMCs compared with wild-type VSMCs following treatment with Fas-L. Addition of recombinant active MMP-7 increased the amount of N-cadherin fragment by 82 and augmented apoptosis by 53. The involvement of MMP-7 was corroborated using human cells, where a MMP-7 selective inhibitor reduced the amount of fragment formed by 51. Importantly, we observed that treatment with Fas-L increased levels of active MMP-7 by 80. Finally, we observed significantly increased cleavage of N-cadherin, MMP-7 activity, and apoptosis in human atherosclerotic plaques compared with control arteries, and a significant reduction in apoptosis in atherosclerotic plaques from MMP-7 knockout mice. Conclusion This study demonstrates that MMP-7 is involved in the cleavage of N-cadherin and modulates VSMC apoptosis, and may therefore contribute to plaque development and rupture.</abstract><qualityIndicators><score>9</score><pdfVersion>1.5</pdfVersion><pdfPageSize>595.276 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>5</keywordCount><abstractCharCount>1780</abstractCharCount><pdfWordCount>5561</pdfWordCount><pdfCharCount>35436</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>251</abstractWordCount></qualityIndicators><title>MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis</title><genre><json:string>research-article</json:string></genre><host><volume>87</volume><publisherId><json:string>cardiovascres</json:string></publisherId><pages><last>146</last><first>137</first></pages><issn><json:string>0008-6363</json:string></issn><issue>1</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1755-3245</json:string></eissn><title>Cardiovascular Research</title></host><categories><wos><json:string>CARDIAC & CARDIOVASCULAR SYSTEMS</json:string></wos></categories><publicationDate>2010</publicationDate><copyrightDate>2010</copyrightDate><doi><json:string>10.1093/cvr/cvq042</json:string></doi><id>650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9</id><score>0.26695943</score><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2010. For permissions please email: journals.permissionsoxfordjournals.org.</p></availability><date>2010-02-05</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis</title><author xml:id="author-1"><persName><forename type="first">Helen</forename><surname>Williams</surname></persName><affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</affiliation></author><author xml:id="author-2"><persName><forename type="first">Jason L.</forename><surname>Johnson</surname></persName><affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</affiliation></author><author xml:id="author-3"><persName><forename type="first">Christopher L.</forename><surname>Jackson</surname></persName><affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</affiliation></author><author xml:id="author-4"><persName><forename type="first">Stephen J.</forename><surname>White</surname></persName><affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</affiliation></author><author xml:id="author-5"><persName><forename type="first">Sarah J.</forename><surname>George</surname></persName><email>s.j.george@bris.ac.uk</email></author></analytic><monogr><title level="j">Cardiovascular Research</title><idno type="pISSN">0008-6363</idno><idno type="eISSN">1755-3245</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-07-01"></date><biblScope unit="volume">87</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="137">137</biblScope><biblScope unit="page" to="146">146</biblScope></imprint></monogr><idno type="istex">650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9</idno><idno type="DOI">10.1093/cvr/cvq042</idno><idno type="ArticleID">cvq042</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010-02-05</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Aims Vascular smooth muscle cell (VSMC) apoptosis can lead to thinning of the fibrous cap and plaque instability. We previously showed that cellcell contacts mediated by N-cadherin reduce VSMC apoptosis. This study aimed to determine whether matrix-degrading metalloproteinase (MMP)-dependent N-cadherin cleavage causes VSMC apoptosis. Methods and results Induction of human VSMC apoptosis using different approaches, including 200 ng/mL Fas ligand (Fas-L) and culture in suspension, caused N-cadherin cleavage and resulted in the appearance of a C-terminal fragment of N-cadherin (35 kDa). Appearance of this fragment during apoptosis was inhibited by 47 with the broad-spectrum MMP inhibitor BB-94. We observed retarded cleavage of N-cadherin after treatment with Fas-L in aortic mouse VSMCs lacking MMP-7. Furthermore, VSMC apoptosis, measured by quantification of cleaved caspase-3, was 43 lower in MMP-7 knockout mouse VSMCs compared with wild-type VSMCs following treatment with Fas-L. Addition of recombinant active MMP-7 increased the amount of N-cadherin fragment by 82 and augmented apoptosis by 53. The involvement of MMP-7 was corroborated using human cells, where a MMP-7 selective inhibitor reduced the amount of fragment formed by 51. Importantly, we observed that treatment with Fas-L increased levels of active MMP-7 by 80. Finally, we observed significantly increased cleavage of N-cadherin, MMP-7 activity, and apoptosis in human atherosclerotic plaques compared with control arteries, and a significant reduction in apoptosis in atherosclerotic plaques from MMP-7 knockout mice. Conclusion This study demonstrates that MMP-7 is involved in the cleavage of N-cadherin and modulates VSMC apoptosis, and may therefore contribute to plaque development and rupture.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Vascular smooth muscle</term></item><item><term>Apoptosis</term></item><item><term>Atherosclerosis</term></item><item><term>Matrix-degrading metalloproteinase-7</term></item><item><term>N-cadherin</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2010-02-05">Created</change><change when="2010-07-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">cardiovascres</journal-id><journal-id journal-id-type="hwp">cardiovascres</journal-id><journal-title>Cardiovascular Research</journal-title><issn pub-type="ppub">0008-6363</issn><issn pub-type="epub">1755-3245</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/cvr/cvq042</article-id><article-id pub-id-type="publisher-id">cvq042</article-id><article-categories><subj-group subj-group-type="heading"><subject>ORIGINAL ARTICLES</subject></subj-group></article-categories><title-group><article-title>MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Williams</surname><given-names>Helen</given-names></name></contrib><contrib contrib-type="author"><name><surname>Johnson</surname><given-names>Jason L.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Jackson</surname><given-names>Christopher L.</given-names></name></contrib><contrib contrib-type="author"><name><surname>White</surname><given-names>Stephen J.</given-names></name></contrib><contrib contrib-type="author"><name><surname>George</surname><given-names>Sarah J.</given-names></name><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff><institution>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary</institution>, <addr-line>Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW</addr-line>, <country>UK</country></aff><author-notes><corresp id="cor1"><label>*</label>Corresponding author. Tel: <phone>+44 117 3423154</phone>; fax: <fax>+44 117 3423581</fax>, Email: <email>s.j.george@bris.ac.uk</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>7</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>5</day><month>2</month><year>2010</year></pub-date><volume>87</volume><issue>1</issue><fpage>137</fpage><lpage>146</lpage><history><date date-type="received"><day>22</day><month>7</month><year>2009</year></date><date date-type="rev-recd"><day>26</day><month>1</month><year>2010</year></date><date date-type="accepted"><day>29</day><month>1</month><year>2010</year></date></history><permissions><copyright-statement>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org.</copyright-statement><copyright-year>2010</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.</p></license></permissions><abstract><sec><title>Aims</title><p>Vascular smooth muscle cell (VSMC) apoptosis can lead to thinning of the fibrous cap and plaque instability. We previously showed that cell–cell contacts mediated by N-cadherin reduce VSMC apoptosis. This study aimed to determine whether matrix-degrading metalloproteinase (MMP)-dependent N-cadherin cleavage causes VSMC apoptosis.</p></sec><sec><title>Methods and results</title><p>Induction of human VSMC apoptosis using different approaches, including 200 ng/mL Fas ligand (Fas-L) and culture in suspension, caused N-cadherin cleavage and resulted in the appearance of a C-terminal fragment of N-cadherin (∼35 kDa). Appearance of this fragment during apoptosis was inhibited by 47% with the broad-spectrum MMP inhibitor BB-94. We observed retarded cleavage of N-cadherin after treatment with Fas-L in aortic mouse VSMCs lacking MMP-7. Furthermore, VSMC apoptosis, measured by quantification of cleaved caspase-3, was 43% lower in MMP-7 knockout mouse VSMCs compared with wild-type VSMCs following treatment with Fas-L. Addition of recombinant active MMP-7 increased the amount of N-cadherin fragment by 82% and augmented apoptosis by 53%. The involvement of MMP-7 was corroborated using human cells, where a MMP-7 selective inhibitor reduced the amount of fragment formed by 51%. Importantly, we observed that treatment with Fas-L increased levels of active MMP-7 by 80%. Finally, we observed significantly increased cleavage of N-cadherin, MMP-7 activity, and apoptosis in human atherosclerotic plaques compared with control arteries, and a significant reduction in apoptosis in atherosclerotic plaques from MMP-7 knockout mice.</p></sec><sec><title>Conclusion</title><p>This study demonstrates that MMP-7 is involved in the cleavage of N-cadherin and modulates VSMC apoptosis, and may therefore contribute to plaque development and rupture.</p></sec></abstract><kwd-group><kwd>Vascular smooth muscle</kwd><kwd>Apoptosis</kwd><kwd>Atherosclerosis</kwd><kwd>Matrix-degrading metalloproteinase-7</kwd><kwd>N-cadherin</kwd></kwd-group><custom-meta-wrap><custom-meta><meta-name>primary-review-time</meta-name><meta-value><bold>Time for primary review: 34 days</bold></meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis</title></titleInfo><name type="personal"><namePart type="given">Helen</namePart><namePart type="family">Williams</namePart><affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jason L.</namePart><namePart type="family">Johnson</namePart><affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher L.</namePart><namePart type="family">Jackson</namePart><affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stephen J.</namePart><namePart type="family">White</namePart><affiliation>Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sarah J.</namePart><namePart type="family">George</namePart><affiliation>E-mail: s.j.george@bris.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2010-07-01</dateIssued><dateCreated encoding="w3cdtf">2010-02-05</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Aims Vascular smooth muscle cell (VSMC) apoptosis can lead to thinning of the fibrous cap and plaque instability. We previously showed that cellcell contacts mediated by N-cadherin reduce VSMC apoptosis. This study aimed to determine whether matrix-degrading metalloproteinase (MMP)-dependent N-cadherin cleavage causes VSMC apoptosis. Methods and results Induction of human VSMC apoptosis using different approaches, including 200 ng/mL Fas ligand (Fas-L) and culture in suspension, caused N-cadherin cleavage and resulted in the appearance of a C-terminal fragment of N-cadherin (35 kDa). Appearance of this fragment during apoptosis was inhibited by 47 with the broad-spectrum MMP inhibitor BB-94. We observed retarded cleavage of N-cadherin after treatment with Fas-L in aortic mouse VSMCs lacking MMP-7. Furthermore, VSMC apoptosis, measured by quantification of cleaved caspase-3, was 43 lower in MMP-7 knockout mouse VSMCs compared with wild-type VSMCs following treatment with Fas-L. Addition of recombinant active MMP-7 increased the amount of N-cadherin fragment by 82 and augmented apoptosis by 53. The involvement of MMP-7 was corroborated using human cells, where a MMP-7 selective inhibitor reduced the amount of fragment formed by 51. Importantly, we observed that treatment with Fas-L increased levels of active MMP-7 by 80. Finally, we observed significantly increased cleavage of N-cadherin, MMP-7 activity, and apoptosis in human atherosclerotic plaques compared with control arteries, and a significant reduction in apoptosis in atherosclerotic plaques from MMP-7 knockout mice. Conclusion This study demonstrates that MMP-7 is involved in the cleavage of N-cadherin and modulates VSMC apoptosis, and may therefore contribute to plaque development and rupture.</abstract><subject><genre>keywords</genre><topic>Vascular smooth muscle</topic><topic>Apoptosis</topic><topic>Atherosclerosis</topic><topic>Matrix-degrading metalloproteinase-7</topic><topic>N-cadherin</topic></subject><relatedItem type="host"><titleInfo><title>Cardiovascular Research</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0008-6363</identifier><identifier type="eISSN">1755-3245</identifier><identifier type="PublisherID">cardiovascres</identifier><identifier type="PublisherID-hwp">cardiovascres</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>87</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>137</start><end>146</end></extent></part></relatedItem><identifier type="istex">650B2EDC9DE7E19A4DC3C65A2F68F86C7FE1F2D9</identifier><identifier type="DOI">10.1093/cvr/cvq042</identifier><identifier type="ArticleID">cvq042</identifier><accessCondition type="use and reproduction" contentType="copyright">Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2010. 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