Carvedilol inhibits platelet-derived growth factor-induced signal transduction in human cardiac fibroblasts.
In the current study, first the platelet-derived growth factor (PDGF)-induced stimulation of the PDGF-beta receptor kinase in human cardiac fibroblasts was examined, and then the possibility of counterbalancing this signal transduction by carvedilol, a beta-blocker with alpha1-blocking properties, was investigated. Human cardiac fibroblasts were cultured from myocardial biopsy samples taken from patients with idiopathic dilated cardiomyopathy. The stimulation of the PDGF-beta receptor kinase by recombinant human PDGF (BB) in the cells and the inhibitory effect of carvedilol (1, 5, 10, and 20 microM) were investigated by analyzing PDGF-induced PDGF receptor tyrosine phosphorylation using Western blotting and by measuring DNA synthesis with a colorimetric assay. In human cardiac fibroblasts, the PDGF receptor kinase could be stimulated with PDGF (100 ng/ml) and inhibited with carvedilol (5 microM). In addition, carvedilol at a concentration of 5 microM significantly decreased DNA synthesis by approximately 50%. The inhibition of PDGF-stimulated mitogenesis by carvedilol at concentrations of 10 and 20 microM was 64 or 75%, respectively. Other beta-adrenoceptor antagonists such as propranolol (10 microM) and metoprolol (10 microM) did not significantly affect the PDGF-induced beta-receptor autophosphorylation. These findings provide novel experimental support for the known beneficial clinical effects of carvedilol in the treatment of chronic heart failure associated with myocardial fibrosis.
Lotze
Ulrich
U
Department of Internal Medicine I (Cardiology, Angiology, Pneumology), Hospital Waltershausen-Friedrichroda, Reinhardsbrunner Strasse 14-17, D-99894 Friedrichroda, Germany. Med1.Lotze@krankenhaus-waltershausen-friedrichroda.de
Heinke
Stefan
S
Fritzenwanger
Michael
M
Krack
Andreas
A
Müller
Siegfried
S
Figulla
Hans R
HR
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D010982:Platelet-Derived Growth Factor; D011412:Propanolamines; D011994:Recombinant Proteins; D000077261:Carvedilol; D004247:DNA; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta