Lovastatin blocks basic fibroblast growth factor-induced mitogen-activated protein kinase signaling in coronary smooth muscle cells via phosphatase inhibition.
We have recently reported that the activation of mitogen-activated protein kinase (MAPK) through specific protein kinase C (PKC) isoforms is required for basic fibroblast growth factor (bFGF)-induced proliferation of coronary smooth muscle cells (cSMC). In this study, we investigated the effects of the 3hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase inhibitor lovastatin on bFGF-induced signal transduction in cSMC. The present study shows that lovastatin inhibits bFGF-stimulated DNA synthesis in cSMC, and that this inhibition is reversed by mevalonate (50 micromol/l) and by geranylgeranyl-pyrophosphate (1-5 micromol/l). Although lovastatin prevented Ras farnesylation the amount of bFGF-stimulated MAPK phosphorylation decreased only partially after lovastatin treatment. In addition, lovastatin pretreatment resulted in a sustained phosphorylation of MAPK. We observed a dose-dependent lovastatin-dependent increase in PKC activity, which could be prevented by mevalonate. This increase was comparable to the one induced by calyculin A (2 nmol/l), an inhibitor of protein phosphatase PP-1 and PP-2A. Lovastatin inhibited the expression of the PP-1 protein, which is involved in bFGF-induced DNA synthesis in cSMC. Thus, our data suggest that, lovastatin possibly affects the dephosphorylation processes of PKC and MAPK by inhibition of PP-1/PP-2A protein phosphatases which are involved in the bFGF-induced mitogenesis in cSMC.
Skaletz-Rorowski
A
A
Institute for Arteriosclerosis Research, University of Münster, Germany. skaletz@uni-muenster.de
Müller
J G
JG
Kroke
A
A
Waltenberger
J
J
Pulawski
E
E
Pinkernell
K
K
Breithardt
G
G
D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008387:Marine Toxins; D008798:Mevalonic Acid / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000737:chemistry; D017368:Protein Prenylation; D013997:Time Factors; D018631:ras Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D011106:Polyisoprenyl Phosphates; D020033:Protein Isoforms; D016222:Fibroblast Growth Factor 2; C059041:calyculin A; D004247:DNA; D008148:Lovastatin; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D018631:ras Proteins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid