Document Detail

Angiotensin converting enzyme inhibitors block mitogenic signalling pathways in rat cardiac fibroblasts.
MedLine Citation:
PMID:  10498289     Owner:  NLM     Status:  MEDLINE    
We studied the effects of angiotensin converting enzyme (ACE) inhibitors on angiotensin II (Ang II) induced growth related signalling pathways in neonatal rat cardiac fibroblasts. In BrdU proliferation assays, Ang II (10(-9)-10(-7) M) stimulated cardiac fibroblast growth in a dose-dependent fashion (maximum at 10(-7) M, 5.22 +/- 0.01-fold, n = 9). 2-2-(1-(ethoxycarbonyl)-3-phenylpropyl)[amino-oxopropyl]-6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid (moexiprilat) led to a dose-dependent inhibition of the Ang II induced cardiac fibroblast growth. A less pronounced effect on cellular proliferation was seen with the ACE inhibitor enalaprilat. To elucidate the mechanisms involved in this direct antiproliferative effect of ACE inhibitors in cardiac fibroblasts, we studied the activation of mitogen-activated protein kinases [MAPKs: extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38-MAPK] and JAK/STAT janus kinases/signal transducer and activator of transcription) signal transduction pathways. Ang II (10(-7) M) caused an increase in MAPKs activity with an increased phosphorylation of ERK1/2 (1.7-fold) and p38-MAPK (3.6-fold). This effect was completely inhibited by moexiprilat (10(-7) M) and enalaprilat (10(-7) M). Stimulation with Ang II (10(-7) M) also led to an increased phosphorylation of STAT3, which is one of the key effector proteins in the JAK/STAT signalling pathway. This effect was also completely inhibited by moexiprilat (10(-7) M) and enalaprilat (10(-7) M). These data show that the ACE inhibitors moexiprilat and enalaprilat inhibit Ang II induced proliferation of cardiac fibroblasts according to their relative potency of ACE inhibition in vitro. This novel effect of ACE inhibitors is accompanied by blocking the Ang II induced activation of several intracellular signal transduction pathways (ERK1/2, p38-MAPK and STAT3).
M van Eickels; C Grohé; K Löbbert; M Stimpel; H Vetter
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Naunyn-Schmiedeberg's archives of pharmacology     Volume:  359     ISSN:  0028-1298     ISO Abbreviation:  Naunyn Schmiedebergs Arch. Pharmacol.     Publication Date:  1999 May 
Date Detail:
Created Date:  1999-09-28     Completed Date:  1999-09-28     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0326264     Medline TA:  Naunyn Schmiedebergs Arch Pharmacol     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  394-9     Citation Subset:  IM    
Medizinische Universitäts-Poliklinik, University of Bonn, Germany.
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MeSH Terms
Angiotensin II / pharmacology
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors / pharmacology*
Animals, Newborn
Benzimidazoles / pharmacology
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
Cell Division / drug effects
Cells, Cultured
DNA-Binding Proteins / pharmacology
Dose-Response Relationship, Drug
Enzyme Activation / drug effects
Flavonoids / pharmacology
Heart / drug effects*
Isoquinolines / pharmacology
Receptor, Angiotensin, Type 1
Receptor, Angiotensin, Type 2
STAT3 Transcription Factor
Signal Transduction / drug effects*
Tetrazoles / pharmacology
Time Factors
Trans-Activators / pharmacology
Reg. No./Substance:
0/2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 0/Angiotensin Receptor Antagonists; 0/Angiotensin-Converting Enzyme Inhibitors; 0/Benzimidazoles; 0/DNA-Binding Proteins; 0/Flavonoids; 0/Isoquinolines; 0/Receptor, Angiotensin, Type 1; 0/Receptor, Angiotensin, Type 2; 0/STAT3 Transcription Factor; 0/Stat3 protein, rat; 0/Tetrahydroisoquinolines; 0/Tetrazoles; 0/Trans-Activators; 11128-99-7/Angiotensin II; EC Protein Kinases; H3753190JS/moexiprilat; S8Q36MD2XX/candesartan

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