NOREPINEPHRINE AND ANG II STIMULATE SECRETION OF TGF-BETA BY NEONATALRAT CARDIAC FIBROBLASTS IN-VITRO

Transforming growth factor-beta (TGF-beta) is a ubiquitous growth-regu lating protein that is capable of influencing the growth and function of heart cells in vitro. To better understand the role TGF-beta might play as a paracrine mediator of cardiac hypertrophy, the expression, s ecretion, and growth effects of TGF-beta were examined. Neonatal cardi ac fibroblasts in vitro secreted latent TGF-beta 1 and TGF-beta 2 as h igh as 15 ng/10(6) cells. Angiotensin II (ANG II) and norepinephrine ( NE) each augmented up to threefold the expression and secretion of lat ent TGF-beta 1 and TGF-beta 2 and also induced a shift in isoform pred ominance from beta 1 to beta 2. Each agent individually produced hyper trophic growth of neonatal cardiocytes and hyperplastic growth of card iac fibroblasts. Paradoxically, the combination of NE and ANG II at in termediate and high concentrations resulted in less TGF-beta secretion (compared with either agent alone) and in hypertrophic growth of fibr oblasts. These results suggest that the growth-promoting effects of AN G II and NE may in part be mediated via a paracrine stimulation of TGF -beta secretion.