Cyclosporine A inhibits induction of DNA synthesis by PDGF and other peptide mitogens in cultured rat aortic smooth muscle cells and dermal fibroblasts

Abstract

The immunosuppressive drug cyclosporine A was recently shown to inhibit smooth muscle proliferation in the vascular response to injury. To examine if this may be due to a direct effect of the drug on the smooth muscle cells (SMCs), we have studied its influence on the phenotypic modulation of rat aortic SMCs in primary cultures and on the induction of DNA synthesis by peptide mitogens in serum-starved subcultures. The results demonstrate that cyclosporine A does not interfere with the transition of the SMCs from a contractile to a synthetic phenotype, an early step in the preparation for cell division. On the other hand, it inhibits induction of DNA synthesis by recombinant platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and insulin-like growth factor-I (IGF-I). Maximum effect was obtained at a concentration of 1-3 micrograms/ml and the drug could be added 4-6 h after the growth factors with full inhibitory effect. No distinct effect on the stimulation of overall RNA and protein synthesis by PDGF-BB was observed, indicating that the drug was not of general cytotoxicity at the concentrations used. Throughout this part of the investigation, similar results were obtained with rat dermal fibroblasts. The findings indicate that cyclosporine A inhibits induction of DNA synthesis by peptide mitogens, and suggest that the inhibitory effect of cyclosporine A on smooth muscle proliferation in vivo at least in part may be due to a direct action on these cells.