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Am J Physiol Cell Physiol 277: C253-C261, 1999;
0363-6143/99 $5.00
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Vol. 277, Issue 2, C253-C261, August 1999

Mechanisms of MAPK activation by bradykinin in vascular smooth muscle cells

Victoria Velarde1, Michael E. Ullian1, Thomas A. Morinelli2, Ronald K. Mayfield1, and Ayad A. Jaffa1,2

1 Department of Medicine and 2 Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina and Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina 29425

Vascular smooth muscle cell (VSMC) proliferation is a prominent feature of the atherosclerotic process occurring after endothelial injury. A vascular wall kallikrein-kinin system has been described. The contribution of this system to vascular disease is undefined. In the present study we characterized the signal transduction pathway leading to mitogen-activated protein kinase (MAPK) activation in response to bradykinin (BK) in VSMC. Addition of 10-10-10-7 M BK to VSMC resulted in a rapid and concentration-dependent increase in tyrosine phosphorylation of several 144- to 40-kDa proteins. This effect of BK was abolished by the B2-kinin receptor antagonist HOE-140, but not by the B1-kinin receptor antagonist des-Arg9-Leu8-BK. Immunoprecipitation with anti-phosphotyrosine antibodies followed by immunoblot revealed that 10-9 M BK induced tyrosine phosphorylation of focal adhesion kinase (p125FAK). BK (10-8 M) promoted the association of p60src with the adapter protein growth factor receptor binding protein-2 and also induced a significant increase in MAPK activity. Pertussis and cholera toxins did not inhibit BK-induced MAPK tyrosine phosphorylation. Protein kinase C downregulation by phorbol 12-myristate 13-acetate and/or inhibitors to protein kinase C, p60src kinase, and MAPK kinase inhibited BK-induced MAPK tyrosine phosphorylation. These findings provide evidence that activation of the B2-kinin receptor in VSMC leads to generation of multiple second messengers that converge to activate MAPK. The activation of this crucial kinase by BK provides a strong rationale to investigate the mitogenic actions of BK on VSMC proliferation in disease states of vascular injury.

B2-kinin receptors; G protein receptors; tyrosine phosphorylation; signal transduction; mitogen-ativated protein kinase


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