ANTISENSE OLIGONUCLEOTIDE TO PROTOONCOGENE C-MYB INHIBITS THE FORMATION OF INTIMAL HYPERPLASIA IN EXPERIMENTAL VEIN GRAFTS

Background: The development of intimal hyperplasia is a major cause of early vein graft failure. The study examines the effects of locally d elivered antisense oligonucleotides to the proto-oncogene c-myb on the development of vein graft intimal hyperplasia. Methods: Common caroti d vein bypass grafting procedures were performed on 60 New Zealand Whi te rabbits. Seventeen grafts were controls, 14 had grafts coated with a commercial gel, 17 had grafts coated with gel containing 200 mu g of an antisense c-myb oligonucleotide, and 6 rabbits each had grafts coa ted with gel containing one of two control oligonucleotides. Grafts we re harvested 28 days after surgery, and sections were taken for dimens ional analysis, morphologic evaluation, and vasomotor function. Grafts were also harvested at 1 day for oligonucleotide uptake/localization analysis and at 3 days for c-myb mRNA analysis. Results: Oligonucleoti des were uniformly distributed within the media and adventitia by 1 da y. A 38% reduction occurred in mean intimal thickness in the vein graf ts coated with antisense to c-myb compared with the other groups. No d ifference in medial thickness was seen among groups. By scanning and t ransmission electron microscopy all vein grafts showed a confluent end othelium. In contrast to control vein grafts, which did not relax to a cetylcholine, most of the gel and all of the gel/oligonucleotide-coate d grafts relaxed by more than 40% of precontracted tension. Responses to a panel of contractile agents were unchanged in the treated groups compared with those in the control group. Conclusions: Locally deliver ed antisense oligonucleotides to proto-oncogene c-myb significantly re duces intimal hyperplasia with preservation of acetylcholine-mediated endothelium-dependent relaxation in experimental vein grafts. These fi ndings suggest that targeting a common regulatory pathway of vascular smooth muscle mitogenesis can be successful in reducing the early deve lopment of intimal hyperplasia.