© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Chronic β2-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism
Integrated Molecular Cardiology Group, Institute for Cardiovascular Research, Worsley Building, University of Leeds, Leeds LS2 9JT, UK
cvsnat{at}leeds.ac.uk
* Corresponding author. Tel.: +44-113-343-4807; fax: +44-113-343-4803.
Objective: The aim of this study was to determine whether chronic β-adrenergic receptor (β-AR) stimulation induces proliferation of human cardiac fibroblasts and to investigate the mechanism(s) involved. Methods and results: In vitro cultures of human cardiac fibroblasts were established from biopsies of right atrial appendage. RT-PCR analysis and pharmacological studies demonstrated that these cells express predominantly the β2-AR subtype coupled to activation of adenylyl cyclase and p44/42 mitogen-activated protein kinase (MAPK). Proliferation was determined by cell counting over a 6-day period in medium containing 2.5% fetal calf serum (control) or supplemented with the non-selective β-AR agonist isoproterenol (ISO). ISO induced a concentration-dependent increase in cardiac fibroblast proliferation, which was maximal at 1 µmol/l. This increased proliferation was inhibited by the β2-AR-selective antagonist ICI-118,551, but not the β1-AR-selective antagonist atenolol. Direct activation of adenylyl cyclase alone (0.1–10 µmol/l forskolin) stimulated cyclic AMP production and MAPK activation, but did not induce cell proliferation. Since catecholamines are not considered to be ‘classical’ growth factors, we subsequently investigated whether β2-AR stimulation results in secretion of growth factors that are able to stimulate proliferation in an autocrine manner. Conditioned medium obtained from cardiac fibroblasts treated with ISO for 48 h increased proliferation of parallel cultures of fibroblasts in the presence of the β-AR antagonist alprenolol. Heat-treatment of this conditioned medium fully prevented the increase in cell proliferation, indicating that the autocrine factor(s) are heat-sensitive proteins. Conclusions: Chronic β2-AR stimulation increases proliferation of human cardiac fibroblasts via a mechanism involving increased secretion of heat-sensitive growth factors.
KEYWORDS Adrenergic (ant)agonists; Cell culture/isolation; Growth factors; Heart failure; Remodeling
1 These authors contributed equally to this work.
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