Effects of fluvastatin on growth of porcine and human vascular smooth muscle cells in vitro.
The effects of fluvastatin, a new fully synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on growth and cell-cycle kinetics of porcine and human vascular smooth muscle cells (SMC) were studied by growth curves and flow cytometric determination of cell-cycle distribution. Growth curves were obtained from counting after 2, 4, 7, 9, 11, and 14 days of incubation in Dulbecco's minimum essential medium and 10% fetal calf serum (FCS). For cell-cycle phase determination, cells were synchronized in G0 by 48 hours of incubation in serum-free medium, then stimulated by incubation in 10% FCS, with or without fluvastatin. There was a concentration-dependent decrease in the proliferation of human and porcine SMC when cells were incubated in the presence of fluvastatin. The reduction in the number of cells was significant with 10(-5) M and 10(-4) M fluvastatin. The G/S-phase transition of human and porcine vascular SMC was reduced to 50% of controls by 10(-4) M fluvastatin, as revealed by cell-cycle analysis. The effects of fluvastatin on growth kinetics and cell-cycle distribution could be completely reversed by the addition of 1 mM mevalonolactone, indicating that the fluvastatin effects are due to specific inhibition of HMG-CoA reductase. The addition of low density lipoprotein as a source of cholesterol failed to support SMC growth and phase transition. Addition of squalene or cholesterol to the culture medium also failed to normalize cell growth. It is concluded that nonsterol products synthesized from mevalonate are necessary for the growth of SMC.(ABSTRACT TRUNCATED AT 250 WORDS)
Rogler
G
G
Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany.
Lackner
K J
KJ
Schmitz
G
G
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002452:Cell Count / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000494:pharmacology; D003470:Culture Media; D003584:Cytological Techniques; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D005434:Flow Cytometry; D000077340:Fluvastatin; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000008:administration & dosage / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D013185:Squalene / Q000494:pharmacology; D013552:Swine
D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D003470:Culture Media; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; C015367:mevalonolactone; D013185:Squalene; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid