Intraplatelet signaling mechanisms of the priming effect of matrix metal loproteinase-2 on platelet aggregation

Objective: Platelets contain and release some matrix metalloproteinases (MMPs), enzymes involved in the degradation of extracellular matrix, and one of these (MMP-2) exerts a proaggregatory effect. We explored the signal transduction mechanisms activated by MMP-2 in human blood platelets. Methods and results: Recombinant, human MMP-2, added before stimulation with subthreshold doses of different agonists, potentiated platelet activation, calcium influx, IP3 formation, and pleckstrin phosphorylation. Wortmann in and LY29400, two PI3-K inhibitors, suppressed the potentiating effects of MMP-2 and preincubation with MMP-2 enhanced the thrombin-induced association of the p85 alpha PI3-K subunit with the cytoskeleton and increased the phosphorylation of PKB. Protein tyrosine kinase inhibitors, MA-P kinase inhibitors, PLA(2) inhibitors, cyclooxygenase inhibitors and antagonists of the P2Y and P2Y12 receptors did not affect the potentiating activity of MMP-2 on platelets. Conclusion: Our data show that MMP-2, at a concentration released by activated platelets, facilitates platelet activation acting at the level of a second messenger system common to different agonists and related to the activation of PI3-K. Platelet-released MMP-2 may contribute to platelet activation in vivo.