Summary

Cell adhesion and proteolytic matrix degradation are centralprocesses in atherosclerosis. Being a member of the family ofADAMs (“a disintegrin and metalloproteinase“), metargidin(ADAM15) combines a metalloproteinase domain and an RGDaminoacid sequence.We studied the potential role of ADAM15as an adhesion receptor on endothelial cells and interactions betweenplatelets and ADAM15 with respect to platelet adhesion,activation and thrombus formation. ADAM15 was found to beexpressed on cultured endothelial cells (HUVEC). Platelet adhesionto immobilized recombinantADAM15 was effectively enhancedunder both static and high shear rate conditions reachingthe maximum level of adhesion to fibrinogen. Consistently,platelet adhesion onto ADAM15 overexpressing endothelialcells was significantly increased. Adhesion to ADAM15 was reduced by blockade of GPIIb-IIIa using neutralizing anti-a IIbß 3mAbs (7E3, 2G12), but not by anti-α_vβ₃ (LM609). SolubleADAM15 binds to activated but not to resting GPIIb-IIIa. Moreover,platelets adherent to ADAM15 additionally attracted plateletsunder high shear rates indicating an initial role of platelet-ADAM15 interactions for thrombus formation. Furthermore,incubation of platelets with solubleADAM15 showed a dose-dependentincrease in secretion of CD62P and CD40L.ADAM15is expressed on endothelial cells and can serve as an adhesionreceptor for platelets via GPIIb-IIIa binding. Platelet adhesion toADAM15 leads to platelet activation, secretion and promotesthrombus formation.Thus,ADAM15 may represent a novel targetfor antithrombotic strategies in cardiovascularpathologies.