Mechanisms of MAPK activation by bradykinin in vascular smooth muscle cells |
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Authors: | Velarde, Victoria Ullian, Michael E. Morinelli, Thomas A. Mayfield, Ronald K. Jaffa, Ayad A. |
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Abstract: | Vascular smooth muscle cell (VSMC) proliferation is a prominentfeature of the atherosclerotic process occurring after endothelial injury. A vascular wall kallikrein-kinin system has been described. Thecontribution of this system to vascular disease is undefined. In thepresent study we characterized the signal transduction pathway leadingto mitogen-activated protein kinase (MAPK) activation in response tobradykinin (BK) in VSMC. Addition of1010-107M BK to VSMC resulted in a rapid and concentration-dependent increasein tyrosine phosphorylation of several 144- to 40-kDa proteins. Thiseffect of BK was abolished by theB2-kinin receptor antagonistHOE-140, but not by the B1-kininreceptor antagonist des-Arg9-Leu8-BK.Immunoprecipitation with anti-phosphotyrosine antibodies followed byimmunoblot revealed that109 M BK induced tyrosinephosphorylation of focal adhesion kinase (p125FAK). BK(108 M) promoted theassociation of p60src with theadapter protein growth factor receptor binding protein-2 and alsoinduced a significant increase in MAPK activity. Pertussis and choleratoxins 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 kinaseinhibited BK-induced MAPK tyrosine phosphorylation. These findingsprovide evidence that activation of theB2-kinin receptor in VSMC leads togeneration of multiple second messengers that converge to activateMAPK. The activation of this crucial kinase by BK provides a strongrationale to investigate the mitogenic actions of BK on VSMCproliferation in disease states of vascular injury. |
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