OBJECTIVE: The aim of this study was to determine whether chronic beta-adrenergic receptor (beta-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 beta(2)-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 beta-AR agonist isoproterenol (ISO). ISO induced a concentration-dependent increase in cardiac fibroblast proliferation, which was maximal at 1 micromol/l. This increased proliferation was inhibited by the beta(2)-AR-selective antagonist ICI-118,551, but not the beta(1)-AR-selective antagonist atenolol. Direct activation of adenylyl cyclase alone (0.1-10 micromol/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 beta(2)-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 beta-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 beta(2)-AR stimulation increases proliferation of human cardiac fibroblasts via a mechanism involving increased secretion of heat-sensitive growth factors.
OBJECTIVE: The aim of this study was to determine whether chronic beta-adrenergic receptor (beta-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 beta(2)-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 beta-AR agonist isoproterenol (ISO). ISO induced a concentration-dependent increase in cardiac fibroblast proliferation, which was maximal at 1 micromol/l. This increased proliferation was inhibited by the beta(2)-AR-selective antagonist ICI-118,551, but not the beta(1)-AR-selective antagonist atenolol. Direct activation of adenylyl cyclase alone (0.1-10 micromol/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 beta(2)-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 beta-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 beta(2)-AR stimulation increases proliferation of human cardiac fibroblasts via a mechanism involving increased secretion of heat-sensitive growth factors.
Authors: Bat-Erdene Myagmar; James M Flynn; Patrick M Cowley; Philip M Swigart; Megan D Montgomery; Kevin Thai; Divya Nair; Rumita Gupta; David X Deng; Chihiro Hosoda; Simon Melov; Anthony J Baker; Paul C Simpson Journal: Circ Res Date: 2017-02-20 Impact factor: 17.367
Authors: Joshua G Travers; Fadia A Kamal; Iñigo Valiente-Alandi; Michelle L Nieman; Michelle A Sargent; John N Lorenz; Jeffery D Molkentin; Burns C Blaxall Journal: J Am Coll Cardiol Date: 2017-08-22 Impact factor: 24.094
Authors: Joshua G Travers; Fadia A Kamal; Jeffrey Robbins; Katherine E Yutzey; Burns C Blaxall Journal: Circ Res Date: 2016-03-18 Impact factor: 17.367
Authors: A Salameh; H Djilali; K Blanke; J Gonzalez Casanova; S von Salisch; A Savtschenko; S Dhein; I Dähnert Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2013-03-03 Impact factor: 3.000
Authors: Kirsten Riches; Michael E Morley; Neil A Turner; David J O'Regan; Stephen G Ball; Chris Peers; Karen E Porter Journal: J Mol Cell Cardiol Date: 2009-06-11 Impact factor: 5.000