Document Detail

Inhibition of rat cardiac fibroblast growth by cAMP--but not by cGMP-dependent protein kinase.
MedLine Citation:
PMID:  11327337     Owner:  NLM     Status:  MEDLINE    
Cardiac fibroblasts play a critical role in the process of pathophysiological cardiac hypertrophy as the cell type responsible for fibrosis. Whereas many growth factors and hormones are thought to be involved, possible crosstalks between signal transduction pathways are not well defined. Therefore we investigated the influence of cAMP- and cGMP-dependent protein kinases (cAK, cGK) on platelet derived growth factor (PDGF) stimulated growth of primary cardiac fibroblasts from adult rats. We show here that PDGF-BB induced cell proliferation can be inhibited by activation of the endogenous cAK directly via the cAMP analog 5,6-DCL-cBIMPS as well as indirectly via the cAMP-elevating receptor agonist prostaglandin-E1 (PGE1). In contrast, activation of the endogenous cGK-I has no influence on cardiac fibroblast cell growth. The strength of the proliferation inhibition is dependent on the time course of cAK activation, i.e., longer activation with the cAMP analog results in stronger proliferation inhibition. No significant influence of cAK or cGK-I on Akt activation or on the short-term activation of the MAPK cascade was observed. In contrast, 5,6-DCI-cBIMPS treatment of cardiac fibroblasts causes an inhibition of long-term MAPK phosphorylation. A prolonged PGE1-dependent cAMP signal after addition of 3-isobutyl-1-methylxanthine (IBMX) blocks the second long-term MAPK phosphorylation as well. Therefore the suppression of MAPK long-term phosphorylation, four to eight hours after PDGF-BB stimulation, appears to play the major role in inhibition of cardiac fibroblast proliferation by cAK activators.
U Marienfeld; U Walter; A Simm
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Basic research in cardiology     Volume:  96     ISSN:  0300-8428     ISO Abbreviation:  Basic Res. Cardiol.     Publication Date:  2001 Apr 
Date Detail:
Created Date:  2001-04-30     Completed Date:  2001-08-23     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0360342     Medline TA:  Basic Res Cardiol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  184-91     Citation Subset:  IM    
Institut für Klinische Biochemie und Pathobiochemie, Würzburg, Germany.
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MeSH Terms
Anticoagulants / pharmacology*
Cell Division / drug effects,  physiology
Cells, Cultured
Cyclic AMP / analogs & derivatives,  pharmacology*
Cyclic GMP-Dependent Protein Kinases / metabolism*
Dichlororibofuranosylbenzimidazole / analogs & derivatives*,  pharmacology
Enzyme Inhibitors / pharmacology*
Fibroblasts / cytology,  enzymology
MAP Kinase Signaling System / drug effects,  physiology
Myocardium / cytology*,  enzymology
Platelet-Derived Growth Factor / pharmacology*
Rats, Wistar
Thionucleotides / pharmacology*
Reg. No./Substance:
0/Anticoagulants; 0/Enzyme Inhibitors; 0/Platelet-Derived Growth Factor; 0/Thionucleotides; 0/platelet-derived growth factor BB; 120912-54-1/5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3',5'-monophosphorothioate; 41941-66-6/8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; 53-85-0/Dichlororibofuranosylbenzimidazole; 60-92-4/Cyclic AMP; EC GMP-Dependent Protein Kinases

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