Abstract
Pravastatin, a HMG-CoA reductase inhibitor was found to inhibit DNA synthesis of vascular smooth muscle cells (VSMC) in a dose-dependent manner. Flow cytometric analysis demonstrated that pravastatin induced G1 arrest. Mevalonate restored the inhibitory effect of pravastatin on DNA synthesis and on cell cycle progression, suggesting the importance of mevalonate itself and/or its metabolites in VSMC proliferation. The major intermediate metabolites of mevalonate, geranylgeranyl-pyrophosphate (GGPP), farnesyl pyrophosphate (FPP) and IPP (isopentenyl pyrophosphate) were prepared in the form of liposomes, and the effects of GGPP, FPP and IPP on pravastatin induced inhibition of VSMC proliferation and G1 arrest were examined. Only GGPP restored the pravastatin-induced inhibition of DNA synthesis and G1 arrest. Pravastatin inhibited translocation of Rho small GTPase from cytosol to membrane. By the addition of GGPP, Rho small GTPase are geranylgeranylated and translocated to membranes during G1/S transition. These data suggest that GGPP, rather than FPP or IPP, is an essential metabolite among mevalonic acid metabolites for VSMC proliferation and the G1/S transition.
MeSH terms
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Animals
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Biological Transport
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Cell Division / drug effects
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Cells, Cultured
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DNA / biosynthesis
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DNA / drug effects
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Dose-Response Relationship, Drug
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Flow Cytometry
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G1 Phase / drug effects
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G1 Phase / physiology*
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GTP-Binding Proteins / drug effects
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism
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Hemiterpenes*
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Immunoblotting
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Liposomes / pharmacology
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Membrane Proteins / drug effects
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Membrane Proteins / genetics
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Muscle, Smooth, Vascular / cytology*
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism*
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Organophosphorus Compounds / metabolism
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Organophosphorus Compounds / pharmacology
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Polyisoprenyl Phosphates / metabolism*
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Polyisoprenyl Phosphates / pharmacology
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Pravastatin / pharmacology
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Rats
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S Phase / drug effects
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S Phase / physiology*
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Sesquiterpenes
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rhoA GTP-Binding Protein
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rhoB GTP-Binding Protein
Substances
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Hemiterpenes
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Liposomes
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Membrane Proteins
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Organophosphorus Compounds
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Polyisoprenyl Phosphates
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Sesquiterpenes
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isopentenyl pyrophosphate
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farnesyl pyrophosphate
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DNA
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GTP-Binding Proteins
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rhoA GTP-Binding Protein
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rhoB GTP-Binding Protein
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Pravastatin
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geranylgeranyl pyrophosphate