Density dependent expression of PDGF-A modulates the angiotensin II dependent proliferation of rat cardiac fibroblasts

The proliferative effect of angiotensin II (Ang-II) on primary cardiac fibroblasts is not well understood and controversially discussed. Results described here show that fibroblasts from adult rat hearts exhibit a cell density dependent Ang-II induced cell proliferation. Whereas we could not detect a proliferative effect of Ang-II on confluent cells, which are still able to divide as shown by stimulation with platelet derived growth factor (PDGF), we observed an Ang-II induced cell division of approximately 20% in non-confluent cells. At both densities, signal transduction molecules such as the mitogen activated protein kinases (MAPK) are activated. There has been substantial evidence that Ang-II may induce the expression and secretion of several growth factors. We demonstrated an approximately fivefold increase in platelet derived growth factor-A (PDGF-A) chain and transforming growth factor beta 1 (TGF-beta 1) mRNA-expression within non-confluent cardiac fibroblasts by semiquantitative reverse polymerase chain reaction, RT-PCR. In contrast, the mRNA-expression of basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), PDGF-A/-B chains, and TGF-beta 1 remained unchanged within confluent cardiac fibroblasts. Experiments with neutralizing antibodies showed that PDGF-AA is an important growth factor regulating cell proliferation, whereas TGF-beta 1 interferes with cell size regulation. In summary, we could show that the Ang-II induced cell proliferation in adult cardiac fibroblasts is mainly due to cell density dependent expression of growth factors like PDGF-AA.