MMP-7 Mediates Cleavage of N-cadherin and Promotes Smooth Muscle Cell Apoptosis

H Williams, JL Johnson, CL Jackson, SJ White, SJ George

Research output: Contribution to journalArticle (Academic Journal)peer-review

72 Citations (Scopus)

Abstract

AIMS: 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. Methods and Results Induction of human VSMC apoptosis using different approaches, including 200ng/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 ( approximately 35kDa). 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 to 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. CONCLUSIONS: 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.
Translated title of the contributionMMP-7 Mediates Cleavage of N-cadherin and Promotes Smooth Muscle Cell Apoptosis
Original languageEnglish
Pages (from-to)137 - 146
Number of pages10
JournalCardiovascular Research
Volume87
Issue number1
Early online date5 Feb 2010
DOIs
Publication statusPublished - 1 Jul 2010

Bibliographical note

Publisher: Oxford Journals

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