Felodipine inhibits nuclear translocation of p42/44 mitogen-activated protein kinase and human smooth muscle cell growth.
OBJECTIVE
Smooth muscle cell (SMC) proliferation contributes to vascular structural changes in cardiovascular disease. Ca(2+) 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 Ca(2+) 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 Ca(2+) antagonist.


CONCLUSIONS
Activation of p42/44mapk, subsequent nuclear translocation and activation of Elk-1 are essentially associated with human SMC proliferation. The Ca(2+) antagonist felodipine prevents p42/44mapk nuclear translocation (but not its activation) associated with inhibition of human SMC growth.
Yang
Zhihong
Z
Vascular Biology, Institute of Physiology, University of Fribourg, Fribourg, Switzerland.
Madinova
Anna
A
Kozai
Toshiyuki
T
Joch
Hana
H
Aebi
Ueli
U
Lüscher
Thomas F
TF
D000077214:Becaplermin; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015736:Felodipine / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D018613:Microscopy, Confocal; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D014178:Translocation, Genetic
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D019950:Mitogen-Activated Protein Kinase 1; D015736:Felodipine