Transient interaction of activated platelets with endothelial cells induces expression of monocyte-chemoattractant protein-1 via a p38 mitogen-activated protein kinase mediated pathway: Implications for atherogenesis

Objective: Activated platelets induce alterations of chemotactic and adhesi ve properties of endothelial cells, a critical initial step in atherogenesi s. We investigated the effect of transient interaction of activated platele ts with cultured human umbilical vein endothelial cells (HUVECs) on secreti on of monocyte chemoattractant protein-1 (MCP-1), a key molecule in monocyt e chemotaxis and transmigration. Methods and results: Transient interaction of alpha -thrombin-activated platelets with endothelial cells for 10-120 m in substantially induced endothelial secretion of MCP-1, monocyte chemotaxi s and adhesion to HUVECs. Platelet-induced secretion of MCP-1 and monocyte- endothelium adhesion was reduced by the MAP kinase p38-specific inhibitor S B203580, but not by other kinase inhibitors including PD98059, wortmannin, or rapamycin. In addition, activated platelets induced transcription of a l uciferase reporter construct containing a MCP-1 promotor, an effect that co uld be inhibited by SB203580. Overexpression of dominant-negative mutants o f MAP kinase p38, CSBP2-(D168A) and CSBP2-(T180E;Y182E) reduced platelet-in duced expression of MCP-1. Conclusions: Activation of the p38 MAP kinase an d consecutive endothelial secretion of MCP-1 induced through transient inte raction of activated platelets might play an important role in atherogenesi s. (C) 2001 Elsevier Science B.V. All rights reserved.