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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<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>
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<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>
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<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>
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<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>
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<copyright-year>2010</copyright-year>
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<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>
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<titleInfo type="alternative" contentType="CDATA"><title>MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis</title>
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<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>
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<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>
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<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>
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<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>
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</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>
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<dateIssued encoding="w3cdtf">2010-07-01</dateIssued>
<dateCreated encoding="w3cdtf">2010-02-05</dateCreated>
<copyrightDate encoding="w3cdtf">2010</copyrightDate>
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<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>
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<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>
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<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. For permissions please email: journals.permissionsoxfordjournals.org.</accessCondition>
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