TROPHIC EFFECTS OF ANGIOTENSIN-II ON NEONATAL RAT CARDIAC MYOCYTES ARE MEDIATED BY CARDIAC FIBROBLASTS

Cultured neonatal rat cardiac fibroblasts (NF) and myocytes (NM) were used to examine the distribution of angiotensin II (ANG II) receptors and the potential role of NF in mediating the trophic response to ANG II in the heart. In NM preparations cultured for 2-5 days, specific bi nding to I-125-ANG II was < 10% of the specific binding in cultured NF . Binding assays, immunocytochemistry, and autoradiography in NM cultu red for > 5 days identified two populations of cells, one with fibrobl ast-like morphology and high density of ANG II receptors and another w ith low binding, comparable to NM cultures at day 5 or earlier. Condit ioned medium (CM) from untreated NF increased cell surface area and ne t [H-3]leucine (Leu) incorporation 1.4-fold in NM. CM from ANG II-trea ted NF enhanced [H-3]Leu incorporation 2.2-fold in NM. This potentiati ng effect of ANG II was inhibited by losartan and was absent when ANG II was added directly to NM. In addition, studies using antibodies and bioassay for transforming growth factor-beta(1) (TGF-beta(1)) suggest ed that TGF-beta(1) does not mediate the trophic effects of ANG II on NM. We conclude that ANG II receptors are localized predominantly on N F and that ANG II can indirectly stimulate hypertrophy of NM by stimul ating NF to produce a transferrable factor(s). These data suggest that cardiac fibroblasts may play a critical role in mediating the hypertr ophic response to ANG II in the rat heart.