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Matrix Metalloproteinase-2 in Platelet Adhesion to Fibrinogen: Interactions With Nitric Oxide

Alfredo Martinez, Eduardo Salas, Anna Radomski, Marek W Radomski

Med Sci Monit 2001; 7(4): BR646-651

ID: 421090

BACKGROUND: Matrix metalloproteinase-2 (MMP-2) has been shown to activatea non-thromboxane, non-ADP pathway of platelet aggregation. In contrast, nitric oxide (NO) is known toinhibit platelet adhesion and aggregation. Therefore, we have studied the release of MMP-2 during plateletadhesion to fibrinogen, the effects of phenanthrolione, an MMP-2 inhibitor, on adhesion and the interactionsof inhibitor with a NO donor, S-nitroso-N-acetyl-D, L-penicillamine (SNAP).
MATERIAL AND METHODS: Humanplatelets were isolated from blood of healthy volunteers and platelet adhesion to fibrinogen-coated plateswas studied by measuring thrombin-stimulated release of platelet a-granule constituent, platelet factor4. In addition, the mode of action of phenanthroline and NO on platelets was investigated by assayingthe levels of intraplatelet cyclic GMP.
RESULTS: Thrombin-stimulated platelet adhesion to fibrinogen wasassociated with increased release of MMP-2 from platelets. Phenanthroline (0.1-100 KM) reduced plateletadhesion to fibrinogen. The adhesion was also inhibited by SNAP (0.1-100 KM), an effect abolished by1H-[1,2,4] oxadiazolol [4,3,-a] quinoxalin-1-one (ODQ), a selective inhibitor of the soluble guanylatecyclase. Co-administration of phenanthroline and SNAP resulted in a synergistic inhibition of plateletadhesion, an effect that was not associated with enhanced cyclic GMP generation by platelets. Furthermore,ODQ did not reverse the synergistic effect of these compounds on adhesion.
CONCLUSIONS: 1. MMP-2 promotesplatelet adhesion to fibrinogen. 2. Phenanthroline and NO synergize to inhibit platelet adhesion to fibrinogenacting through a cyclic GMP-independent mechanism(s).

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