title: Extracellular matrix proteins in cardiac fibroblasts derived from rat hearts with chronic pressure overload: effects of beta-receptor blockade.
abstract: Left ventricular hypertrophy (LVH) is accompanied by progressive accumulations of extracellular matrix proteins. They are produced predominantly by cardiac fibroblasts that surround the cardiac myocytes. The aim of this study was to emphasize the role of a combined approach using both in vivo and in vitro studies to elucidate the effects of carvedilol on cardiac remodeling. We therefore used an established model of supravalvular aortic banding and cardiac fibroblasts. LVH was induced by banding of the ascending aorta. Male Wistar rats were allocated to four groups: sham-operated, sham+carvedilol, aortic stenosis (AS), and AS+carvedilol. Treatment time was four weeks. Fibroblasts were isolated from the entire left ventricle of sham and AS rats. Carvedilol/metoprolol/prazosin were added (0.1, 1.0 and 10 microM; 24 h). In addition, interferon- gamma was applied for 24 h (10, 100 and 1000 IU). AS rats revealed increased LV weights (+27%) and cardiomyocyte widths as compared to sham-operated rats (1.6-fold, P<0.01). Carvedilol reduced LVH by 20%. This finding was accompanied by a decrease of laminin, fibronectin, collagen I and III in vivo. Collagen I/III and fibronectin were increased in fibroblasts of AS v sham rats (P<0.0001, each). Carvedilol reduced collagen I, III and fibronectin by 40/60/35% (0.1 microM; P<0.001) irrespective of LVH. Carvedilol had no effects on collagen IV and laminin. Carvedilol dose-dependently reduced the proliferation rate by 20% at 0.1 microM(P<0.0001). Metoprolol and prazosin had no effect on the expression of extracellular matrix proteins and on the proliferation of the cells of either origin. Interferon- gamma blunted the proliferation rate of cultured fibroblasts and lead to a significant decrease in extracellular matrix deposits. These results indicate that the effects of carvedilol may be due to the antiproliferative or antioxidative properties of this unselective beta-adrenergic receptor antagonist. These changes of the extracellular matrix represent a new mechanism of carvedilol that may contribute to the observed beneficial effects in congestive heart failure.
authors.affiliation: Institut für Klinische Pharmakologie und Toxikologie, Benjamin Franklin Medical Center, Freie Universität Berlin, Garystr. 5, D-14195 Berlin, Germany. dgrimm@zedat.fu-berlin.de
authors.forename: D
authors.initials: D
authors.lastname: Grimm
authors.forename: M
authors.initials: M
authors.lastname: Huber
authors.forename: H C
authors.initials: HC
authors.lastname: Jabusch
authors.forename: M
authors.initials: M
authors.lastname: Shakibaei
authors.forename: S
authors.initials: S
authors.lastname: Fredersdorf
authors.forename: M
authors.initials: M
authors.lastname: Paul
authors.forename: G A
authors.initials: GA
authors.lastname: Riegger
authors.forename: E P
authors.initials: EP
authors.lastname: Kromer
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002227:Carbazoles / Q000378:metabolism* / Q000494:pharmacology; D000077261:Carvedilol; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008790:Metoprolol / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism / Q000494:pharmacology; D011412:Propanolamines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017725:Ventricular Pressure
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002227:Carbazoles; D016326:Extracellular Matrix Proteins; D011412:Propanolamines; D000077261:Carvedilol; D007371:Interferon-gamma; D008790:Metoprolol; D011224:Prazosin