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Non‐canonical MMP1‐PAR1 signaling drives vascular smooth muscle cell de‐differentiation and restenosis
Author(s) -
Austin Karyn,
Javid Golrokh,
Kuliopulos Athan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1096.1
Subject(s) - restenosis , vascular smooth muscle , proteases , intimal hyperplasia , thrombin , neointima , receptor , matrix metalloproteinase , fibrous cap , microbiology and biotechnology , phenotype , medicine , biology , endocrinology , cancer research , smooth muscle , platelet , stent , gene , biochemistry , enzyme
Cardiovascular disease remains the leading cause of death in the United States. Aberrant vascular repair following plaque rupture or iatrogenic intervention is mediated by smooth muscle cells (SMCs). SMC proliferation, migration, and de‐differentiation from a contractile to a synthetic phenotype are crucial contributors to the pathology associated with maladaptive remodeling. The GPCR, protease activated receptor‐1 (PAR1), has been implicated in both vascular remodeling and atherothrombosis. Despite the well documented contribution of PAR1 to arterial thrombosis, it is unclear whether PAR1 promotes or mitigates the hyperplastic response to arterial injury. We sought to determine whether inhibition of upstream activating proteases of PAR1, matrix metalloprotease‐1 (MMP‐1) and thrombin, would have differing effects on SMC behavior and restenosis. We describe a previously unknown pathway through which MMP‐1 drives intimal hyperplasia and leads to SMC de‐differentiation through biased agonism of PAR1. In contrast, thrombin‐PAR1 signaling promotes a contractile phenotype. Also, pharmacologic blockade of MMP‐1 suppresses intimal hyperplasia following arterial injury. These data suggest a new strategy for targeted PAR1 inhibition that does not rely on receptor antagonism, but instead directly targets the detrimental activating protease. NIH grants F30 HL108590 (to K.M.A.), R01 HL64701 (to A.K.)