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Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site

Vishal Trivedi1, Adrienne Boire, Boris Tchernychev

  • 1Department of Medicine, Tufts University School of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.

Cell
|April 22, 2009
PubMed

Insights

Platelet matrix metalloprotease-1 (MMP-1) activates protease-activated receptor-1 (PAR1) on platelets, promoting aggregation. Blocking this MMP-1-PAR1 interaction may prevent arterial thrombosis.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Hematology

Background:

  • Matrix metalloproteases (MMPs) are involved in various physiological and pathological processes.
  • MMPs were traditionally viewed as matrix-degrading enzymes but possess signaling roles.
  • Platelet MMPs influence hemostasis and survival, but their mechanisms are unclear.

Purpose of the Study:

  • To investigate the signaling role of platelet MMP-1 in platelet activation and function.
  • To elucidate the interaction between MMP-1 and its receptors on platelets.
  • To assess the therapeutic potential of targeting the MMP-1-PAR1 axis in thrombosis.

Main Methods:

  • Investigated MMP-1 activation on platelet surfaces upon collagen exposure.
  • Analyzed MMP-1 cleavage of protease-activated receptor-1 (PAR1).
  • Assessed downstream signaling pathways including Rho-GTP, cell shape change, and MAPK signaling.
  • Evaluated the effect of MMP1-PAR1 blockade on thrombogenesis in vitro and in vivo.

Main Results:

  • Platelet MMP-1 activates PAR1 on the platelet surface.
  • MMP-1 cleaves PAR1 at a unique site, activating Rho-GTP pathways, cell shape change, and MAPK signaling.
  • Activation of MMP-1 by fibrillar collagen promotes platelet aggregation via PAR1.
  • Inhibition of the MMP1-PAR1 interaction reduced thrombogenesis under arterial flow and in animal models.

Conclusions:

  • Platelet MMP-1 directly signals through PAR1, linking matrix metalloproteinase activation to G protein signaling in platelets.
  • The MMP1-PAR1 pathway is crucial for platelet aggregation and thrombogenesis.
  • Targeting the MMP1-PAR1 interaction presents a potential strategy for preventing arterial thrombosis.

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