Hydrogen peroxide-and fetal bovine serum-induced DNA synthesis in vascular smooth muscle cells: positive and negative regulation by protein kinase C isoforms

AbstractHydrogen peroxide and fetal bovine serum stimulate DNA synthesis in growth-arrested smooth muscle cells with remarkably similar kinetics and cell density dependence. However, while stimulation with fetal bovine serum results in cell proliferation, that by H202 is followed by cell death. Depletion of conventional and novel protein kinase C isoforms, resulting from a long treatment with phorbol-l2-myristate- 13-acetate, further increases H202-induced DNA synthesis. On the other hand, the specific protein kinase C inhibitor calphostin C abolished the increased DNA synthesis promoted by fetal bovine serum or H202. H202 increases protein kinase C activity in smooth muscle cells. This effect is markedly reduced, but not abolished, by down-regulation of the α, δ and ϵ protein kinase C isoforms. Thus, the ζ isoform of protein kinase C, which is not down-regulated, may be responsible for the residual H202 stimulation of protein kinase C. In conclusion, the results obtained show that H202 stimulates protein kinase C activity and DNA synthesis in growth-arrested smooth muscle cells: these events are not followed by cell proliferation but rather by cell death. This H202 stimulated DNA synthesis appears to be negatively controlled by α, δ and ϵ isoforms and positively controlled by the ζ isoform of protein kinase C