Differential effects of protein kinase C on human vascular smooth muscle cell proliferation and migration

Vascular smooth muscle cell (SMC) migration and proliferation contribute to intimal hyperplasia, and protein kinase C (PKC) may be required for both e vents. In this report, we investigated the role of PKC in proliferation and migration of SMC derived from the human saphenous vein. Activation of PKC by phorbol-12,13-dibutyrate (PDBu) or (-)-indolactam [( -)- ILV] increases SMC proliferation. Downregulation of PKC activity by prolonged incubation w ith phorbol ester or inhibition of PKC with chelerythrine in SMC diminished agonist-stimulated proliferation. In contrast, stimulation of PKC with PDB u or (-)- ILV inhibited basal and agonist-induced SMC chemotaxis. Moreover, downregulation of PKC or inhibition with chelerythrine accentuated migrati on. We postulated that the inhibitory effect of PKC on SMC chemotaxis was m ediated through cAMP-dependent protein kinase (protein kinase A, PKA). In s upport of this hypothesis, we found that activation of PKC in SMC stimulate d PKA activity. The cAMP agonist forskolin significantly inhibited SMC chem otaxis. Furthermore, the inhibitory effect of PKC on SMC chemotaxis was com pletely reversed by cAMP or PKA inhibitors. In search of the PKC isotype(s) underlying these differential effects of PKC in SMC, we identified eight i sotypes expressed in human SMC. Only PKC-alpha,-betaI, -delta, and -epsilon were eliminated by downregulation, suggesting that one or more of these fo ur enzymes facilitate the observed phorbol ester-dependent effects of PKC i n SMC. In summary, we found that PKC activation enhances proliferation but inhibits migration of human vascular SMC. These differential effect of PKC on vascular cells appears to be mediated through PKC-alpha,-betaI, -delta, and/or -epsilon.