Matrix metalloproteases and PAR1 activation

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.

Figure 1

MMP-PAR1 signaling in vascular diseases. PAR1 senses a diverse milieu of extracellular proteases and subsequently relays that information to influence cellular behavior and potentially exacerbate disease pathologies. The N-terminal extracellular domain (exodomain) of PAR1 is cleaved at a canonical site by thrombin and noncanonical sites by MMP-1 and MMP-13. Various signaling outputs can lead to platelet thrombosis, atherosclerosis, in-stent restenosis, heart failure, and sepsis.

Figure 2

MMP-PAR1 interactions. (A) Structure of the proMMP1 zymogen. The catalytic zinc is indicated as a red ball within the catalytic domain. (B) Cleavage sites for MMP-1, MMP-13, and thrombin in PAR1 and resulting tethered ligands. (C) Top: N-terminal region encompassing the PAR1-tethered ligand showing the cleavage sites for MMP-1 and thrombin. Bottom: Structural model of the catalytic groove of MMP-1 bound to the N-terminal domain of PAR1, illustrating the catalytic zinc coordinated to the PAR1 scissile D-P bond. The model was created using the x-ray structures of MMP-1 and MMP-8 bound to peptide inhibitors as templates.^,

Figure 3

MMP and PAR1 expression in atherothrombotic disease. Specific MMPs and PAR1 and their cellular sources in an atherosclerotic blood vessel. Instability of the fibrous cap overlaying the plaque can lead to subendothelial collagen exposure and subsequent platelet activation. Platelets express MMP-1, -2, -3, and -14^,, and exposure of naive platelets to collagen activates MMP-1 from the proMMP1 zymogen. Endothelial cells express a number of MMPs, including MMP-1, -2, -9, -13, and -14. Macrophages and smooth muscle cells (SMCs) are activated (Mφ foam cells and SMCs with red nuclei) by the proinflammatory state resulting from cholesterol deposition in the plaque body and secrete MMP-1, -2,-9, and -13, among others.^,