ANGIOTENSIN-II STIMULATES THE AUTOCRINE PRODUCTION OF TRANSFORMING GROWTH-FACTOR-BETA-1 IN ADULT-RAT CARDIAC FIBROBLASTS

Angiotensin II (Ang II) has been implicated in the development of card iac hypertrophy and myocardial fibrosis. While recent in vivo and in v itro studies performed in cultured cardiac myocytes and fibroblasts su pport this role for Ang II, the mechanisms of Ang II action at the cel lular level remain unclear. In the present study, we postulated that A ng II action in adult cardiac fibroblasts may stimulate the autocrine production and release of transforming growth factor-beta 1 (TGF-beta 1), a known regulator of cardiac fibroblast and myocyte function. We e xamined the ability of Ang II to regulate the gene expression, biologi cal activity, and protein production of TGF-beta 1 in cultured adult r at cardiac fibroblasts. Treatment of fibroblast cultures with Ang II ( 10(-9) M) induced a two-fold increase in TGF-beta 1 mRNA levels within 4 h that was sustained through 24 h (P<0.01). TGF-beta 1-like activit y in Ang II-treated cultures was significantly increased compared with control as measured by bioassay (p<0.001). Specificity for TGF-beta(1 )-like activity was confirmed through its neutralization with a TGF-be ta 1 specific antibody (100 mu g/ml). Total concentration of TGF-beta 1 (latent plus active forms) in conditioned media from Ang II-treated cardiac fibroblasts was also found to be greater than control (P<0.01) . These findings suggest that the effects of Ang II in the adult myoca rdium may be mediated in part by autocrine/paracrine mechanisms, inclu ding the production and release of TGF-beta 1 by cardiac fibroblasts. (C) 1995 Academic Press Limited