Abstract
We have previously demonstrated that (1) vascular smooth muscle cells (SMC) isolated from atherosclerotic lesions express a characteristic gene of macrophages, macrophage colony-stimulating factor receptor (c-fms), and (2) a combination of epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)-BB induces stable expression of c-fms gene in normal vascular SMC to the level of that isolated from atherosclerotic lesions. To study the transcriptional regulation of c-fms expression in normal vascular SMC in response to PDGF and EGF, transcription activity of c-fms promotor was examined. In the deletion analysis of c-fms promotor, we demonstrated that PU. 1 binding element at -178 by to -165 by relative to the translation starting site, was required for full transcription activity in normal vascular SMC. Mutation in the PU. 1 binding element markedly reduced the promotor activity, suggesting that PU. 1 binding site plays an important role in the c-fms expression. Furthermore, we demonstrated that PU. 1 mRNA was induced in normal vascular SMC after treatment with PDGF and EGF, and that antisense oligonucleotide, targeted against 5' untranslated region including the ATG initiator codon of PU. 1 cDNA, inhibited growth factor-induced c-fms expression. These results indicated that multiple growth factors regulated the phenotypic transformation of medial smooth muscle cells to macrophage-like cells in atherosclerotic lesions by regulation c-fms expression through the interaction with PU. 1.
