Thrombin activates p38 mitogen-activated protein kinase in vascular smooth muscle cells

被引:30
作者
Kanda, Y [1 ]
Nishio, E [1 ]
Kuroki, Y [1 ]
Mizuno, K [1 ]
Watanabe, Y [1 ]
机构
[1] Natl Def Med Coll, Dept Pharmacol, Tokorozawa, Saitama 3598513, Japan
关键词
thrombin; p38 mitogen-activated protein kinase; vascular smooth muscle cells; DNA synthesis;
D O I
10.1016/S0024-3205(01)00990-0
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Thrombin is a potent mitogen for vascular smooth muscle cells. However, the signaling pathways by which thrombin mediates its mitogenic response are not fully understood. The ERK (extracellular signal-regulated protein kinase) and JNK (c-Jun N-terminal kinase) members of the mitogen-activated protein kinase (MAPK) family are reported to be activated by thrombin. We have investigated the response to thrombin of another member of the MAPK family, p38 MAPK, which has been suggested to be activated by both stress and inflammatory stimuli in vascular smooth muscle cells. We found that thrombin induced 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) thrombin. GF109203X, a protein kinase C inhibitor, and prolonged treatment with phorbol 12-myristate 13-acetate partially inhibited p38 MAPK activation. A tyrosine 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). p38 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 inhibitor, SB203580, on thrombin-induced proliferation. SB203580 inhibited thrombin-induced DNA synthesis in a dose-dependent manner. These results suggest 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 Science Inc. All rights reserved.
引用
收藏
页码:1989 / 2000
页数:12
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