Thrombin activates p38 mitogen-activated protein kinase in vascular smoothmuscle cells

Thrombin is a potent mitogen for vascular smooth muscle cells. However, the signaling pathways by which thrombin mediates its mitogenic response are n ot fully understood. The ERK (extracellular signal-regulated protein kinase ) and JNK (c-Jun N-terminal kinase) members of the mitogen-activated protei n kinase (MAPK) family are reported to be activated by thrombin. We have in vestigated the response to thrombin of another member of the MAPK family, p 38 MAPK, which has been suggested to be activated by both stress and inflam matory stimuli in vascular smooth muscle cells. We found that thrombin indu ced time- and dose-dependent activation of p38 MAPK. Maximal stimulation of p38 MAPK was observed after a 10-min incubation with 1 unit ml(-1) thrombi n. GF109203X, a protein kinase C inhibitor, and prolonged treatment with ph orbol 12-myristate 13-acetate partially inhibited p38 MAPK activation. A ty rosine kinase inhibitor, genistein, also inhibited p38 MAPK activation in a dose-dependent manner. p38 MAPK activation was inhibited by overexpression of beta ARK1ct (beta -adrenergic receptor kinase 1 C-terminal peptide). p3 8 MAPK activation was also inhibited by expression of dominant-negative Ras , not by dominant-negative Rac. We next examined the effect of a p38 MAPK i nhibitor, SB203580, on thrombin-induced proliferation. SB203580 inhibited t hrombin-induced DNA synthesis in a dose-dependent manner. These results sug gest that thrombin activates p38 MAPK in a manner dependent on G beta gamma , protein kinase C, a tyrosine kinase, and Ras, that p38 MAPK has a role in thrombin-induced mitogenic response in the cells. (C) 2001 Elsevier Scienc e Inc. All rights reserved.