Document Detail


Simvastatin inhibits cell cycle progression in glucose-stimulated proliferation of aortic vascular smooth muscle cells by up-regulating cyclin dependent kinase inhibitors and p53.
MedLine Citation:
PMID:  18804536     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Simvastatin was reported to attenuate platelet-derived growth factor (PDGF)-induced vascular smooth muscle proliferation by up-regulation of cyclin dependent kinase (CDK) inhibitor p27, but had no effect on p16, p21, p53 expression. We investigate the mechanisms by which simvastatin inhibits vascular smooth muscle cell (VSMC) growth in high glucose conditions to mimic diabetes. Simvastatin was added to A7r5 cells cultured in high glucose (25 mM) medium, mimicking diabetes. We used an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate cell viability; flow cytometric analysis for cell counts distribution in the cell cycle; and Western blot, immunoblotting, and immunoprecipitation analyses to evaluate the effects of simvastatin on CDK activity and cell cycle regulatory proteins. Cell counts were significantly increased in G0/G1 phase and significantly decreased in S and G2/M phases. In our study, low dose of simvastatin had no significant inhibitory effect on VSMC growth in normal glucose condition. However, both low and high doses of simvastatin inhibited VSMC growth significantly in a dose-dependent manner in high glucose status. We also found that simvastatin inhibited phosphorylation of Rb, promoted expression of p53, p16, p21, p27 and decreased CDK2/4 activity. In conclusion, simvastatin inhibits VSMC proliferation in high glucose status, mimicking diabetes, inducing a G0/G1 phase cell cycle growth arrest by acting on multiple steps upstream of pRb, including inhibition of CDK2/4 expression and up-regulation of p53, p21, p16, and p27. We propose that statins may be used more extensively in diabetic patients regardless of lipid status for preventing atherosclerosis and restenosis after PCI.
Authors:
Kuei-Chuan Chan; Chau-Jong Wang; Hsieh-Hsun Ho; Hsiang-Mei Chen; Chien-Ning Huang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-09-02
Journal Detail:
Title:  Pharmacological research : the official journal of the Italian Pharmacological Society     Volume:  58     ISSN:  1043-6618     ISO Abbreviation:  Pharmacol. Res.     Publication Date:    2008 Sep-Oct
Date Detail:
Created Date:  2008-10-30     Completed Date:  2009-01-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8907422     Medline TA:  Pharmacol Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  247-56     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, Institute of Medicine, Chung-Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Road, Taichung 402, Taiwan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aorta, Thoracic / cytology,  drug effects
Benzothiazoles / pharmacology
Blotting, Western
Cell Cycle / drug effects*
Cell Line
Cell Proliferation / drug effects
Cell Survival / drug effects
Cyclin-Dependent Kinase Inhibitor Proteins / biosynthesis*,  genetics
Flow Cytometry
Glucose / pharmacology*
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Immunoprecipitation
Myocytes, Smooth Muscle / drug effects*
Rats
Simvastatin / pharmacology*
Tetrazolium Salts
Thiazoles
Toluene / analogs & derivatives,  pharmacology
Tumor Suppressor Protein p53 / antagonists & inhibitors,  biosynthesis*,  genetics
Chemical
Reg. No./Substance:
0/Benzothiazoles; 0/Cyclin-Dependent Kinase Inhibitor Proteins; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Tetrazolium Salts; 0/Thiazoles; 0/Tumor Suppressor Protein p53; 0/pifithrin; 108-88-3/Toluene; 298-93-1/thiazolyl blue; 50-99-7/Glucose; 79902-63-9/Simvastatin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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