PDGF-AA, A POTENT MITOGEN FOR CARDIAC FIBROBLASTS FROM ADULT-RATS

The heart responds to increased haemodynamic load with growth of the v entricles. The rise in ventricle mass is due to increasing mass of the myocytes and proliferation of fibroblasts and smooth muscle cells. Th e accompanying adaptation and remodelling of the interstitium, e.g. pr oduction and composition of the extracellular matrix proteins, determi ne a physiological or pathophysiological hypertrophy. Fibroblasts play a critical role in this process as the producers of extracellular mat rix proteins. So far the growth factors involved are not well defined, and therefore we investigated the effect of platelet-derived growth f actor (PDGF) isoforms on cellular proliferation of fibroblasts from ad ult rat hearts. Unlike other cell types of the cardiovascular system ( e.g. smooth muscle cells), PDGF-AA has an extraordinarily high stimula tory effect on cell growth of these fibroblasts. It induces cell divis ion 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 e xpress an unusually high number of PDGF alpha-receptors, (15 300 PDGF alpha-receptors, 24 800 PDGF beta-receptors per cell) which could expl ain this effect. The alpha-receptors display a lower and shorter autop hosphorylation after stimulation with PDGF in comparison to the beta-r eceptors. The activation of the MAP kinase pathway is not different af ter stimulation with both PDGF isoforms. Interestingly, quiescent card iac fibroblasts contain a preactivated p70(s6)-kinase. The specific dr ug rapamycin not only inhibits the p70(s6)-kinase activation but also PDGF induced cell proliferation for more than 50%. Because the p70(s6) -kinase activation is implicated in growth regulation in this cell sys tem, the preactivation of this kinase is discussed to be a possible ex planation for the enhanced growth effect of PDGF-AA. (C) 1997 Academic Press Limited.