Intraplatelet signaling mechanisms of the priming effect of matrix metalloproteinase-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.


RESULTS
Recombinant, human MMP-2, added before stimulation with subthreshold doses of different agonists, potentiated platelet activation, calcium influx, IP3 formation, and pleckstrin phosphorylation. Wortmannin 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 p85alpha PI3-K subunit with the cytoskeleton and increased the phosphorylation of PKB. Protein tyrosine kinase inhibitors, MAP kinase inhibitors, PLA2 inhibitors, cyclooxygenase inhibitors and antagonists of the P2Y1 and P2Y12 receptors did not affect the potentiating activity of MMP-2 on platelets.


CONCLUSIONS
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.
Falcinelli
E
E
Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy.
Guglielmini
G
G
Torti
M
M
Gresele
P
P
D000730:Androstadienes / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004357:Drug Synergism; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010974:Platelet Aggregation / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015290:Second Messenger Systems / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D002118:Calcium; D002867:Chromones; D004963:Estrenes; D007211:Indoles; D015544:Inositol 1,4,5-Trisphosphate; D020778:Matrix Metalloproteinase 2; D061965:Matrix Metalloproteinase Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011760:Pyrrolidinones; D011994:Recombinant Proteins; D013917:Thrombin; D019716:Tissue Inhibitor of Metalloproteinase-2; D010738:Type C Phospholipases; D000077191:Wortmannin; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C064758:Ro 31-8220