Document Detail

Effects of HMG-CoA reductase inhibition on PDGF- and angiotensin II- mediated signal transduction: suppression of c-Jun and c-Fos in human smooth muscle cells in vitro.
MedLine Citation:
PMID:  10205288     Owner:  NLM     Status:  MEDLINE    
Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors were shown to be effective in primary and secondary prevention of coronary heart disease. The beneficial effect of statins is generally attributed to their cholesterol lowering activity. However recent work points to additional cholesterol independent effects of these drugs on cellular signal transduction. In this study it was investigated whether HMG-CoA reductase inhibition could affect induction of the transcription factors c-Jun and c-Fos in smooth muscle cells, which play an important role in atherogenesis. SMC were preincubated for 12 h with or without lovastatin (5 microM) and subsequently stimulated with platelet derived growth factor (PDGF, 10 ng/ml) or angiotensin II (0.1 microM) for 1, 2, 4 and 12 h or with phorbol myristate acetate (100 pM) for 2 h. Stimulation in the absence of the HMG-CoA reductase inhibitor led to a significant induction of c-Jun and c-Fos. Lovastatin inhibited, PDGF-, angiotensin II- and PMA-mediated induction. Concomitant addition of mevalonate, farnesylpyrophosphate and geranylgeranylpyrophosphate prevented the effects of HMG-CoA reductase inhibition resulting in rescued expression of c-Jun and c-Fos. The suppression of these transcription factors was associated with a complete growth arrest. Viability was not affected by pretreatment with the HMG-CoA reductase inhibitor. The data demonstrate that lovastatin can suppress PDGF- and angiotensin II-mediated induction of c-Jun and c-Fos protein in human SMC. This inhibitory effect may prevent activation of numerous growth factor- and cell cycle- genes. Whether these findings contribute to the effects of statins in atherosclerosis remains to be further investigated.
J Kreuzer; L Watson; T Herdegen; M Loebe; P Wende; K Kübler
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of medical research     Volume:  4     ISSN:  0949-2321     ISO Abbreviation:  Eur. J. Med. Res.     Publication Date:  1999 Apr 
Date Detail:
Created Date:  1999-07-06     Completed Date:  1999-07-06     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9517857     Medline TA:  Eur J Med Res     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  135-43     Citation Subset:  IM    
Universität Heidelberg, Innere Medizin III, Bergheimer Str. 58, D-69115 Heidelberg, Germany.
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MeSH Terms
Angiotensin II / pharmacology
Arteriosclerosis / metabolism,  prevention & control
Cell Division / drug effects
Cells, Cultured
Cholesterol / metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Muscle, Smooth, Vascular / cytology,  drug effects*,  metabolism*
Platelet-Derived Growth Factor / pharmacology
Proto-Oncogene Proteins c-fos / biosynthesis*
Proto-Oncogene Proteins c-jun / biosynthesis*
Signal Transduction / drug effects
Reg. No./Substance:
0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Platelet-Derived Growth Factor; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 11128-99-7/Angiotensin II; 57-88-5/Cholesterol

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

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