Role Of Ras/Pkc Xi/Mek/Erk1/2 Signaling Pathway In Angiotensin Ii-Induced Vascular Smooth Muscle Cell Proliferation

The role of protein kinase C (PKC) and its cross talk with extracellular signal-regulated kinase (ERK) cascade in angiotensin 11 (AngII)-elicited vascular smooth muscle cell (VSMC) proliferation are still unclear. In this study, the PKC pathway of AngII to activate ERK1/2 and induce cell proliferation was investigated in rat aortic smooth muscle cells. The proliferation of VSMCs was tested by [H-3]-thymidine incorporation assay. Phosphorylated and non-phosphorylated PKC zeta, ERK1/2, Elk-1, and mitogen-activated ERK-activating kinase (MEK) were estimated by Western blot analysis. The interactions of signal molecules were examined by immunoprecipitation. AngII-induced VSMC proliferation and activation of ERK1/2 and nuclear transcription factor Elk-1 were all down-regulated by PKC non-specific inhibitor (staurosporine) and PKC zeta pseudosubstrate inhibitor (PS-PKC zeta). Dominant negative Ras transfection into VSMCs decreased AngII-induced PKC zeta and ERK1/2 phosphorylation. AngII stimulated the association of PKC zeta with Ras. AngII-induced MEK phosphorylation was inhibited by PKC zeta pseudosubstrate inhibitor and the PKC zeta-MEK complex was detected by immunoprecipitation. These results suggest that PKC zeta isoform is involved in VSMC proliferation and Elk-1 activation. AngII can activate ERK1/2 by Ras/PKC zeta/MEK pathway, which may be one of the important signal transduction pathways in AngII-induced VSMC proliferation. (c) 2004 Elsevier B.V. All rights reserved.