PMID- 20139113
OWN - NLM
STAT- MEDLINE
DCOM- 20100920
LR  - 20211020
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Print)
IS  - 0008-6363 (Linking)
VI  - 87
IP  - 1
DP  - 2010 Jul 1
TI  - MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis.
PG  - 137-46
LID - 10.1093/cvr/cvq042 [doi]
AB  - 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 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 (approximately 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.
FAU - Williams, Helen
AU  - Williams H
AD  - Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Research 
      Floor Level 7, Upper Maudlin St., Bristol BS2 8HW, UK.
FAU - Johnson, Jason L
AU  - Johnson JL
FAU - Jackson, Christopher L
AU  - Jackson CL
FAU - White, Stephen J
AU  - White SJ
FAU - George, Sarah J
AU  - George SJ
LA  - eng
GR  - FS/07/053/24069/BHF_/British Heart Foundation/United Kingdom
GR  - PG/05/103/19684/BHF_/British Heart Foundation/United Kingdom
GR  - PG/05/103/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100205
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Antigens, CD)
RN  - 0 (Apolipoproteins E)
RN  - 0 (CDH2 protein, human)
RN  - 0 (Cadherins)
RN  - 0 (Cdh2 protein, mouse)
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Thiophenes)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - BK349F52C9 (batimastat)
RN  - EC 3.4.22.- (Casp3 protein, mouse)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.24.23 (MMP7 protein, human)
RN  - EC 3.4.24.23 (Matrix Metalloproteinase 7)
SB  - IM
MH  - Animals
MH  - Antigens, CD/*metabolism
MH  - Apolipoproteins E/deficiency/genetics
MH  - *Apoptosis
MH  - Atherosclerosis/*enzymology/genetics/pathology
MH  - Cadherins/*metabolism
MH  - Caspase 3/metabolism
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Fas Ligand Protein/metabolism
MH  - Humans
MH  - Matrix Metalloproteinase 7/deficiency/genetics/*metabolism
MH  - Matrix Metalloproteinase Inhibitors
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Muscle, Smooth, Vascular/drug effects/*enzymology/pathology
MH  - Myocytes, Smooth Muscle/drug effects/*enzymology/pathology
MH  - Phenylalanine/analogs & derivatives/pharmacology
MH  - Protease Inhibitors/pharmacology
MH  - Recombinant Proteins/metabolism
MH  - Rupture
MH  - Thiophenes/pharmacology
MH  - Time Factors
PMC - PMC2883897
MID - UKMS29271
OID - NLM: UKMS29271
EDAT- 2010/02/09 06:00
MHDA- 2010/09/21 06:00
PMCR- 2010/02/05
CRDT- 2010/02/09 06:00
PHST- 2010/02/09 06:00 [entrez]
PHST- 2010/02/09 06:00 [pubmed]
PHST- 2010/09/21 06:00 [medline]
PHST- 2010/02/05 00:00 [pmc-release]
AID - cvq042 [pii]
AID - 10.1093/cvr/cvq042 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2010 Jul 1;87(1):137-46. doi: 10.1093/cvr/cvq042. Epub 2010 Feb 
      5.