Ac. Newby et al., INHIBITION OF RABBIT AORTIC SMOOTH-MUSCLE CELL-PROLIFERATION BY SELECTIVE INHIBITORS OF PROTEIN-KINASE-C, British Journal of Pharmacology, 114(8), 1995, pp. 1652-1656
1 We studied the effect of two structurally-related, selective inhibit
ors of protein kinase C, Ro 31-8220 and Ro 31-7549, on the reinitiatio
n of proliferation in quiescent first passage rabbit aortic smooth mus
cle cells in response to (a) the direct activator of protein kinase C,
phorbol dibutyrate (PDBu), (b) platelet-derived growth factor (PDGF),
(c) a combination of PDGF and 5-hydroxytryptamine (5-HT) or (d) serum
. 2 Ro 31-8220 and Ro 31-7549 concentration-dependently inhibited prol
iferation in response to each mitogen. The inhibitory potency (IC50) O
f Ro 31-8220 and Ro 31-7549, respectively, was similar against prolife
ration induced by PDBu (0.55 and 1.1 mu M), PDGF (0.6 and 0.9 mu M), P
DGF and 5-HT (0.68 and 1.1 mu M), although slightly less against serum
(1.7 and 5 mu M). The effects of the protein kinase C inhibitors on p
roliferation could not be ascribed to cytotoxicity. Neither Ro 31-8220
nor Ro 31-7549 (0.3-3 mu M) inhibited PDGF receptor tyrosine phosphor
ylation. 3 The results show that Ro 31-8220 and Ro 31-7549 are potent
inhibitors of smooth muscle cell proliferation in response to a direct
activator of protein kinase C, the defined growth factors, PDGF and 5
-HT, and the complex mixture of mitogens in serum. Protein kinase C ac
tivation thus appears to be an important growth transducing mechanism
for each of these agents.