EFFECT OF PHOSPHOROTHIOATED OLIGONUCLEOTIDES ON NEOINTIMA FORMATION IN THE RAT CAROTID-ARTERY - DISSECTING THE MECHANISM OF ACTION

Several studies have shown that single-dose administration of agents t hat inhibit medial cell replication, such as antisense oligonucleotide s to cell replication genes, can inhibit neointima formation after art erial injury. However, the precise mechanism of action of these agents is unknown. We analyzed the effect of phosphorothioated oligonucleoti des delivered periadventitially on the response to injury in the ballo on-injured rat carotid artery. Antisense oligonucleotides to c-myc sup pressed medial replication 2 days after injury, but this effect was no t present at 4 or 14 days. Endothelial cell proliferation was not affe cted by antisense oligonucleotides. There was, however, a significant suppression of intimal area and intima/media ratio at 14 days and an i ncrease in lumen area in the antisense-treated group. Indeed, an incre ase in the number of medial cells at 14 days in the antisense group in dicated that most of the effect of the agent was due to the suppressio n of cell migration. No effect was noted on expression of two genes, o steopontin and tropoelastin, used as markers of modulation of smooth m uscle cells to a ''neonatal'' phenotype at 4 days after injury. Becaus e no effect on cell proliferation could be demonstrated after 2 days, our data indicate that an early effect of the antisense agent mediates its longer-term effects. We suggest that this effect may be due to th e suppression of migration of medial smooth muscle cells rather than t he suppression of medial or intimal cell proliferation.