Protein kinase C mediates basic fibroblast growth factor-induced proliferation through mitogen-activated protein kinase in coronary smooth muscle cells

Proliferation of coronary smooth muscle cells (cSMCs) contributes to the pa thogenesis of arteriosclerosis and restenosis after angioplasty, and basic fibroblast growth factor (bFGF) is a powerful mitogen for cSMCs. In this st udy, we investigated the involvement of mitogen-activated protein kinase (M APK), protein kinase C (PKC), and the transcription factor c-myc in bFGF-st imulated mitogenesis, as well as the functional relationship between these factors. cSMC stimulation with bFGF resulted in phosphorylation of p42 MAPK , as well as the phosphorylation and increased expression of c-myc. The MAP K kinase (MEK) inhibitor PD98059 blocked bFGF-stimulated MAPK phosphorylati on and resulted in both a decrease of c-myc expression and inhibition of bF GF-stimulated DNA synthesis in cSMCs. bFGF also increased PKC activity in c SMCs in a time-dependent manner. The inhibition of PKC by chelerythrine or its downregulation by phorbol 12-myristate 13-acetate (PMA) inhibited bFGF- induced DNA synthesis and blocked the phosphorylation of MAPK and c-myc exp ression in response to bFGF. This indicates an involvement of phorbol ester -sensitive PKC isoforms in MAPK activation and mitogenic signaling by bFGF. Western blot analysis revealed the presence of the phorbol ester-sensitive isoforms PKC alpha, epsilon, and gamma as well as the PKC isoforms iota, l ambda, mu, and zeta in cSMCs. In this study, we show that the MAPK cascade is required for bFGF-induced proliferation and that phorbol ester-sensitive PKC isoforms contribute to the bFGF-induced cSMC mitogenesis in cSMCs.