Antisense oligonucleotide to proto-oncogene c-myb inhibits the formation of intimal hyperplasia in experimental vein grafts.

Abstract

The development of intimal hyperplasia is a major cause of early vein graft failure. The study examines the effects of locally delivered antisense oligonucleotides to the proto-oncogene c-myb on the development of vein graft intimal hyperplasia. Common carotid vein bypass grafting procedures were performed on 60 New Zealand White rabbits. Seventeen grafts were controls, 14 had grafts coated with a commercial gel, 17 had grafts coated with gel containing 200 micrograms of an antisense c-myb oligonucleotide, and 6 rabbits each had grafts coated with gel containing one of two control oligonucleotides. Grafts were harvested 28 days after surgery, and sections were taken for dimensional 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. Oligonucleotides were uniformly distributed within the media and adventitia by 1 day. A 38% reduction occurred in mean intimal thickness in the vein grafts coated with antisense to c-myb compared with the other groups. No difference in medial thickness was seen among groups. By scanning and transmission electron microscopy all vein grafts showed a confluent endothelium. In contrast to control vein grafts, which did not relax to acetylcholine, most of the gel and all of the gel/oligonucleotide-coated 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. Locally delivered antisense oligonucleotides to proto-oncogene c-myb significantly reduces intimal hyperplasia with preservation of acetylcholine-mediated endothelium-dependent relaxation in experimental vein grafts. These findings suggest that targeting a common regulatory pathway of vascular smooth muscle mitogenesis can be successful in reducing the early development of intimal hyperplasia.