© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Felodipine inhibits nuclear translocation of p42/44 mitogen-activated protein kinase and human smooth muscle cell growth
aVascular Biology, Institute of Physiology, University of Fribourg, Fribourg, Switzerland
bMaurice-Müller Institute of Structural Biology, Biocenter, University of Basel, Basel, Switzerland
cCardiovascular Research, Institute of Physiology, University of Zürich, Zürich, Switzerland
dCardiovascular Center, Division of Cardiology, University Hospital, Ramistrasse 100, CH-8091 Zürich, Switzerland
cardiotfl{at}gmx.ch
* Corresponding author. Tel.: +41-1-255-2121; fax: +41-1-255-4251
Objective: Smooth muscle cell (SMC) proliferation contributes to vascular structural changes in cardiovascular disease. Ca2+ antagonists exert antiproliferative effects and may also be clinically beneficial in the patients. However, the underlying mechanisms of action remain elusive. Activation of mitogen-activated protein kinases (MAPK), in particular p42/44mapk plays a central role in cell proliferation. We hypothesise that Ca2+ antagonists inhibit cell proliferation by interfering with the p42/44mapk pathway in human SMC. Methods: SMC were cultured from human aorta. Cell proliferation was analysed by [3H]thymidine incorporation. Activation of p42/44mapk and the nuclear target protein Elk-1 was analysed by phosphorylation and p42/44mapk nuclear translocation by confocal microscope. Results: PDGF-BB (10 ng/ml) stimulated [3H]thymidine incorporation, phosphorylated p42/44mapk, caused nuclear translocation of the enzymes and phosphorylated the nuclear target protein Elk-1. Felodipine (10–7 to 10–5 mol/l) inhibited [3H]thymidine incorporation to PDGF-BB, had no effect on p42/44mapk phosphorylation. However, p42/44mapk nuclear translocation and Elk-1 activation stimulated by PDGF-BB were prevented by the Ca2+ antagonist. Conclusion: Activation of p42/44mapk, subsequent nuclear translocation and activation of Elk-1 are essentially associated with human SMC proliferation. The Ca2+ antagonist felodipine prevents p42/44mapk nuclear translocation (but not its activation) associated with inhibition of human SMC growth.
KEYWORDS Growth factors; Protein kinases; Protein phosphorylation; Smooth muscle
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