Document Detail


Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture.
MedLine Citation:
PMID:  10856525     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We investigated the influence of lovastatin, simvastatin and pravastatin on proliferation and viability of vascular smooth muscle cells (SMC) in vitro and studied the effects of lovastatin on a mouse SMC line transgenic for a temperature-sensitive mutant of SV40 large T antigen (TAg), known to inhibit the function of p53 and pRb family members. We found that lovastatin and simvastatin inhibited cell proliferation by provoking G0/G1 phase arrest with concomitant depression of the proliferation antigen Ki-67/MIB-1. Lovastatin at high concentrations of 20 micromol/l caused cell death in the presence of serum but not under serum starved conditions, which was verified on the basis of increased DNA strand breaks, decreased DNA content and morphological alterations seen by electron microscopy. Cell death was also found for simvastatin, whereas pravastatin did not exhibit antiproliferative or cytotoxic effects. Mouse SMC transgenic for TAg did not show any impaired sensitivity to the antiproliferative and cell death inducing effect of lovastatin, but both effects could be antagonized by the supplementation of mevalonate. The data indicate that antiproliferative and cytotoxic effects of lovastatin are caused by the using up of products of mevalonate metabolism and do not require the presence of p53 or pRb.
Authors:
J R Sindermann; L Fan; K A Weigel; D Troyer; J G Müller; A Schmidt; K L March; G Breithardt
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Atherosclerosis     Volume:  150     ISSN:  0021-9150     ISO Abbreviation:  Atherosclerosis     Publication Date:  2000 Jun 
Date Detail:
Created Date:  2000-07-27     Completed Date:  2000-07-27     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  0242543     Medline TA:  Atherosclerosis     Country:  IRELAND    
Other Details:
Languages:  eng     Pagination:  331-41     Citation Subset:  IM    
Affiliation:
Institute for Arteriosclerosis Research, Division of Molecular Cardiology, University of Münster, Domagkstrasse 3, 48149, Münster, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, Nuclear
Aorta / drug effects,  metabolism,  ultrastructure
Apoptosis / drug effects
CDC2-CDC28 Kinases*
Cattle
Cell Division / drug effects*
Cell Survival / drug effects*
Cells, Cultured
Coronary Vessels / drug effects,  metabolism,  ultrastructure
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases / metabolism
DNA / biosynthesis,  genetics
Humans
Hydroxymethylglutaryl CoA Reductases / drug effects,  metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
In Situ Nick-End Labeling
Ki-67 Antigen / metabolism
Lovastatin / pharmacology
Mevalonic Acid / pharmacology
Mice
Mice, Transgenic
Muscle, Smooth, Vascular / drug effects*,  metabolism,  ultrastructure
Nuclear Proteins / metabolism
Pravastatin / pharmacology
Protein-Serine-Threonine Kinases / metabolism
Rats
Retinoblastoma Protein / metabolism
Simvastatin / pharmacology
Tumor Suppressor Protein p53 / metabolism
Chemical
Reg. No./Substance:
0/Antigens, Nuclear; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Ki-67 Antigen; 0/Nuclear Proteins; 0/Retinoblastoma Protein; 0/Tumor Suppressor Protein p53; 150-97-0/Mevalonic Acid; 75330-75-5/Lovastatin; 79902-63-9/Simvastatin; 81093-37-0/Pravastatin; 9007-49-2/DNA; EC 1.1.1.-/Hydroxymethylglutaryl CoA Reductases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.22/CDC2-CDC28 Kinases; EC 2.7.11.22/CDK2 protein, human; EC 2.7.11.22/Cdk2 protein, mouse; EC 2.7.11.22/Cdk2 protein, rat; EC 2.7.11.22/Cyclin-Dependent Kinase 2; EC 2.7.11.22/Cyclin-Dependent Kinases

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