Extracellular matrix proteins in cardiac fibroblasts derived from rat hearts with chronic pressure overload: Effects of beta-receptor blockade

Left ventricular hypertrophy (LVH) is accompanied by progressive accumulati ons of extracellular matrix proteins. They are produced predominantly by ca rdiac 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 an d cardiac fibroblasts. LVH was induced by banding of the ascending aorta. M ale Wistar rats were allocated to four groups: sham-operated, sham+carvedil ol, aortic stenosis (AS), and AS + carvedilol. Treatment time was four week s. Fibroblasts wore isolated from the entire left ventricle of sham and AS rats. Carvedilol/metoprolol/prazosin were added (0.1, 1.0 and 10 muM: 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 c ompared 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, c ollagen 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 collage n I, III and fibronectin by 40/60/35% (0.1 muM: P<0.001) irrespective of LV H, Carvedilol had no effects on collagen IV and laminin. Carvedilol dose-de pendently reduced the proliferation rate by 20%: at 0.1 <mu>M (P<0.0001). M etoprolol and prazosin had no effect on the expression of extracellular mat rix proteins and on the proliferation of the cells of either origin. Interf eron-<gamma> blunted the proliferation rate of cultured fibroblasts and lea d to a significant decrease in extracellular matrix deposits. These results indicate that the effects of carvedilol may be due to the antiproliferativ e or antioxidative properties of this unselective beta-adrenergic receptor antagonist. These changes of the extracellular matrix represent a new mecha nism of carvedilol that may contribute to the observed beneficial effects i n congestive heart Failure. (C) 2001 Academic Press.