Inhibition of cultured vascular smooth muscle cell migration by simvastatin (MK-733).
The effect of simvastatin (MK-733), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the migration of cultured porcine smooth muscle cells (SMCs) was investigated in modified Boyden chambers. Platelet-derived growth factor (PDGF) stimulated the SMC migration dose dependently. MK-733 inhibited the migration response induced by PDGF with an IC50 value of 2 microM. Supplementation with mevalonate restored the migration response inhibited by MK-733 but the addition of low-density-lipoprotein (LDL) did not change the response. Another HMG-CoA reductase inhibitor, pravastatin (CS-514), also reduced the migration response. However its potency was far less than that of MK-733. MK-733 also inhibited the SMC migration stimulated by fibrinogen. These results suggest that non-sterol metabolite(s) of mevalonate, possibly prenylated proteins, are involved in a migration signaling pathway and that HMG-CoA reductase inhibitors are effective in the prevention of the formation of intimal hyperplasia in atherosclerosis.
Hidaka
Y
Y
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
Eda
T
T
Yonemoto
M
M
Kamei
T
T
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001013:Aorta, Thoracic; D001596:Benzylamines / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D019821:Simvastatin / Q000031:analogs & derivatives; D013261:Sterols / Q000096:biosynthesis; D013552:Swine; D013876:Thiophenes / Q000494:pharmacology
D000924:Anticholesteremic Agents; D001596:Benzylamines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D010982:Platelet-Derived Growth Factor; D013261:Sterols; D013876:Thiophenes; C066059:NB 598; D005340:Fibrinogen; C063287:simvastatin acid; D008148:Lovastatin; D019821:Simvastatin; D009543:Nifedipine; D017035:Pravastatin; D008798:Mevalonic Acid