PDGF-AA, a Potent Mitogen for Cardiac Fibroblasts from Adult Rats

Abstract

The heart responds to increased haemodynamic load with growth of the ventricles. The rise in ventricle mass is due to increasing mass of the myocytes and proliferation of fibroblasts and smooth muscle cells. The accompanying adaptation and remodelling of the interstitium, e.g. production and composition of the extracellular matrix proteins, determine a physiological or pathophysiological hypertrophy. Fibroblasts play a critical role in this process as the producers of extracellular matrix proteins. So far the growth factors involved are not well defined, and therefore we investigated the effect of platelet-derived growth factor (PDGF) isoforms on cellular proliferation of fibroblasts from adult rat hearts. Unlike other cell types of the cardiovascular system (e.g. smooth muscle cells), PDGF-AA has an extraordinarily high stimulatory effect on cell growth of these fibroblasts. It induces cell division to nearly the same extent and with the same kinetics as PDGF-BB as shown by cell number and flow cytometry. Cardiac fibroblasts do not express an unusually high number of PDGFα-receptors, (15 300 PDGFα-receptors, 24 800 PDGFβ-receptors per cell) which could explain this effect. Theα-receptors display a lower and shorter autophosphorylation after stimulation with PDGF in comparison to theβ-receptors. The activation of the MAP kinase pathway is not different after stimulation with both PDGF isoforms. Interestingly, quiescent cardiac fibroblasts contain a preactivated p70S6-kinase. The specific drug rapamycin not only inhibits the p70S6-kinase activation but also PDGF induced cell proliferation for more than 50%. Because the p70S6-kinase activation is implicated in growth regulation in this cell system, the preactivation of this kinase is discussed to be a possible explanation for the enhanced growth effect of PDGF-AA.