Document Detail

Noncanonical matrix metalloprotease-1-protease-activated receptor-1 signaling triggers vascular smooth muscle cell dedifferentiation and arterial stenosis.
MedLine Citation:
PMID:  23814055     Owner:  NLM     Status:  MEDLINE    
Vascular injury that results in proliferation and dedifferentiation of vascular smooth muscle cells (SMCs) is an important contributor to restenosis following percutaneous coronary interventions or plaque rupture. Protease-activated receptor-1 (PAR1) has been shown to play a role in vascular repair processes; however, little is known regarding its function or the relative roles of the upstream proteases thrombin and matrix metalloprotease-1 (MMP-1) in triggering PAR1-mediated arterial restenosis. The goal of this study was to determine whether noncanonical MMP-1 signaling through PAR1 would contribute to aberrant vascular repair processes in models of arterial injury. A mouse carotid arterial wire injury model was used for studies of neointima hyperplasia and arterial stenosis. The mice were treated post-injury for 21 days with a small molecule inhibitor of MMP-1 or a direct thrombin inhibitor and compared with vehicle control. Intimal and medial hyperplasia was significantly inhibited by 2.8-fold after daily treatment with the small molecule MMP-1 inhibitor, an effect that was lost in PAR1-deficient mice. Conversely, chronic inhibition of thrombin showed no benefit in suppressing the development of arterial stenosis. Thrombin-PAR1 signaling resulted in a supercontractile, differentiated phenotype in SMCs. Noncanonical MMP-1-PAR1 signaling resulted in the opposite effect and led to a dedifferentiated phenotype via a different G protein pathway. MMP-1-PAR1 significantly stimulated hyperplasia and migration of SMCs, and resulted in down-regulation of SMC contractile genes. These studies provide a new mechanism for the development of vascular intimal hyperplasia and suggest a novel therapeutic strategy to suppress restenosis by targeting noncanonical MMP-1-PAR1 signaling in vascular SMCs.
Karyn M Austin; Nga Nguyen; Golrokh Javid; Lidija Covic; Athan Kuliopulos
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-06-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-08-12     Completed Date:  2013-11-01     Revised Date:  2014-08-12    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23105-15     Citation Subset:  IM    
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MeSH Terms
Carotid Stenosis / genetics,  metabolism*,  pathology,  physiopathology,  therapy
Cell Dedifferentiation*
Cell Line
Gene Expression Regulation / drug effects,  genetics
Matrix Metalloproteinase 1 / genetics,  metabolism*
Matrix Metalloproteinase 13 / genetics,  metabolism*
Muscle Contraction / drug effects,  genetics
Myocytes, Smooth Muscle / metabolism*,  pathology
Protease Inhibitors / pharmacology
Receptor, PAR-1 / genetics,  metabolism*
Signal Transduction*
Tunica Intima / metabolism,  pathology
Grant Support
Reg. No./Substance:
0/Protease Inhibitors; 0/Receptor, PAR-1; EC 3.4.24.-/Matrix Metalloproteinase 13; EC 3.4.24.-/Mmp13 protein, mouse; EC protein, human; EC Metalloproteinase 1

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