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 events. 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 with phorbol ester or inhibition of PKC with chelerythrine in SMC diminished agonist-stimulated proliferation. In contrast, stimulation of PKC with PDBu or (-)-ILV inhibited basal and agonist-induced SMC chemotaxis. Moreover, downregulation of PKC or inhibition with chelerythrine accentuated migration. We postulated that the inhibitory effect of PKC on SMC chemotaxis was mediated through cAMP-dependent protein kinase (protein kinase A, PKA). In support of this hypothesis, we found that activation of PKC in SMC stimulated PKA activity. The cAMP agonist forskolin significantly inhibited SMC chemotaxis. Furthermore, the inhibitory effect of PKC on SMC chemotaxis was completely reversed by cAMP or PKA inhibitors. In search of the PKC isotype(s) underlying these differential effects of PKC in SMC, we identified eight isotypes expressed in human SMC. Only PKC-alpha, -beta I, -delta, and -epsilon were eliminated by downregulation, suggesting that one or more of these four enzymes facilitate the observed phorbol ester-dependent effects of PKC in 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, -beta I, -delta, and/or -epsilon.
Itoh
H
H
Division of Vascular Surgery, New York Hospital and Cornell University Medical Center, New York 10021, USA.
Yamamura
S
S
Ware
J A
JA
Zhuang
S
S
Mii
S
S
Liu
B
B
Kent
K C
KC
D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism / Q000494:pharmacology*
D007527:Isoenzymes; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C