The inhibitory mechanisms of amlodipine in human vascular smooth muscle cell proliferation.
The abnormal proliferation of vascular smooth muscle cells (VSMCs) is closely related to vascular diseases. There is growing evidence that calcium antagonists inhibit VSMC growth/proliferation, yet their molecular mechanisms remain to be determined. Recent reports suggest that p42/p44 mitogen-activated protein kinases (MAPKs) play an important role in cell growth and proliferation induced by growth factors. This study was designed to determine whether these MAPKs are involved in VSMC proliferation induced by basic fibroblast growth factor (bFGF) and to examine the inhibitory effect of amlodipine. Human VSMCs were obtained from inner mammary artery. p42/p44 MAPKs activity was measured by immunoblotting assay using anti-p42/p44 phospho-MAPK antibody. 1) bFGF (20 ng/ml) significantly activated p42/p44 MAPKs with a peak time of 5-15 min, which was maintained for 3 h. PD98059 (100 nM-10 microM), a specific inhibitor of MAPK kinase, inhibited bFGF-induced p42/p44 MAPKs activation in a dose-dependent manner. 2) Amlodipine (1-100 nM) dose-dependently inhibited p42/p44 MAPKs activation by bFGF. 3) Amlodipine (10 nM) could inhibit both short-term and long-term p42/p44 MAPKs activation by bFGF. Our results indicate that bFGF could activate p42/p44 MAPKs. Amlodipine, which could inhibit bFGF-induced human VSMC proliferation, inhibited both short-term and sustained p42/p44 MAPKs activation by bFGF, suggesting that bFGF-induced VSMC proliferation may be related to p42/p44 MAPKs activation, and that the antiproliferative effect of amlodipine may be related to its inhibition of p42/p44 MAPKs activation.
Zhang
Y Z
YZ
Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Second Medical University, PR China.
Gao
P J
PJ
Wang
X Y
XY
Stepien
O
O
Marche
P
P
Zhang
Z L
ZL
Zhu
D L
DL
D017311:Amlodipine / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology; D013997:Time Factors
D004791:Enzyme Inhibitors; D005419:Flavonoids; D016222:Fibroblast Growth Factor 2; D017311:Amlodipine; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one