Role of Ras/PKCzeta/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 II (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 [3H]-thymidine incorporation assay. Phosphorylated and non-phosphorylated PKCzeta, 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 PKCzeta pseudosubstrate inhibitor (PS-PKCzeta). Dominant negative Ras transfection into VSMCs decreased AngII-induced PKCzeta and ERK1/2 phosphorylation. AngII stimulated the association of PKCzeta with Ras. AngII-induced MEK phosphorylation was inhibited by PKCzeta pseudosubstrate inhibitor and the PKCzeta-MEK complex was detected by immunoprecipitation. These results suggest that PKCzeta isoform is involved in VSMC proliferation and Elk-1 activation. AngII can activate ERK1/2 by Ras/PKCzeta/MEK pathway, which may be one of the important signal transduction pathways in AngII-induced VSMC proliferation.
Zhao
Yali
Y
Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100083, China.
Liu
Jie
J
Li
Li
L
Liu
Limei
L
Wu
Liling
L
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation; D047468:Immunoprecipitation; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
D000804:Angiotensin II; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins