Abstract |
Cardiovascular diseases, including atherothrombosis, are the leading cause of morbidity and mortality in the United States, Europe, and the developed world. Matrix metalloproteases ( MMPs) have recently emerged as important mediators of platelet and endothelial function, and atherothrombotic disease. Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor that is classically activated through cleavage of the N-terminal exodomain by the serine protease thrombin. Most recently, 2 MMPs have been discovered to have agonist activity for PAR1. Unexpectedly, MMP-1 and MMP-13 cleave the N-terminal exodomain of PAR1 at noncanonical sites, which result in distinct tethered ligands that activate G-protein signaling pathways. PAR1 exhibits metalloprotease-specific signaling patterns, known as biased agonism, that produce distinct functional outputs by the cell. Here we contrast the mechanisms of canonical ( thrombin) and noncanonical ( MMP) PAR1 activation, the contribution of MMP-PAR1 signaling to diseases of the vasculature, and the therapeutic potential of inhibiting MMP-PAR1 signaling with MMP inhibitors, including atherothrombotic disease, in- stent restenosis, heart failure, and sepsis.
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Authors | Karyn M Austin, Lidija Covic, Athan Kuliopulos |
Journal | Blood
(Blood)
Vol. 121
Issue 3
Pg. 431-9
(Jan 17 2013)
ISSN: 1528-0020 [Electronic] United States |
PMID | 23086754
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
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Chemical References |
- Receptor, PAR-1
- Matrix Metalloproteinases
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Topics |
- Animals
- Atherosclerosis
(metabolism)
- Humans
- Matrix Metalloproteinases
(metabolism)
- Receptor, PAR-1
(metabolism)
- Signal Transduction
(physiology)
- Thrombosis
(metabolism)
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