INHIBITION OF SMOOTH-MUSCLE CELL-PROLIFERATION AND MIGRATION IN-VITROBY ANTISENSE OLIGONUCLEOTIDE TO C-MYB

Purpose: Smooth muscle cell (SMC) migration and proliferation are prom inent features of intimal hyperplasia. Previous studies have shown tha t inhibition of c-myb inhibits arterial. SMC proliferation. Our goal w as to evaluate the effect of an antisense oligonucleotide targeted to c-myb on the proliferation and migration of SMC explanted from synthet ic vascular grafts. Methods: SMCs were enzymatically removed from aort as and Dacron grafts explanted from dogs (n = 5). for proliferation st udies, quiescent SMCs were incubated with either 0.0, 0.5, 5.0, or 10. 0 mu M antisense (GTGTCGGGGTCTCCGGGC) or sense (GCCCGGAGACCCCGACAC) ol igonucleotides to c-myb. Proliferation was measured after 24 hours by incorporation of [H-3]thymidine. Migration was assessed 24 hours after a razor injury. Results: Antisense to c-myb consistently inhibited pr oliferation and migration of both native aortic and graft SMCs in a do se-dependent fashion. At a concentration of 10 mu M antisense oligonuc leotide, aortic and graft SMC proliferation rates were 32% +/- 20% and 56% +/- 9% of control samples, respectively, At 25 mu M antisense, th e number of migrating aortic and graft SMCs decreased to 41.9% +/- 26. 8% and 51.9% +/- 34.1% of control samples, respectively. Conclusions:: Our results suggest that antisense oligonucleotides to c-myb may be u seful in the inhibition of SMC proliferation and migration associated with development of intimal hyperplasia.