[Effects on myointimal proliferation of an antisense oligonucleotide directed against c-myb: specificity of action and consequences on vasoreactivity].

Abstract

Several reports have shown that an antisense oligonucleotide directed against c-myb (AS 18) inhibits the proliferation of smooth muscle cell. The aims of this study were to confirm the specificity of a new c-myb antisens and to evaluate changes in vasoreactivity following treatment with a c-myb antisense. Five groups of rats were constituted. All underwent desendothelialisation of the abdominal aorta. A solution containing pluronic gel, or one of the following oligonucleotides: AS 18, 15 mere antisense directed against c-myb, an aleatory 4G sequence containing 4 consecutive guanosines, a 15 mere antisense mismatch (n = 11), was applied around the aorta. After 21 days, the thickness and mean surface areas of the media and intima were calculated. Four groups of rats were constituted for the reactivity study: control (A), desendothelialisation (B), desendothelialisation + application of AS 18 (C), and application of AS 18 alone (D). One ring per aorta was sampled at the 21st day and analysed in an organ chamber. The following results were obtained: the thickness and average surface areas of the intima were smaller (p < 0.05) in the 4G and AS 18 groups; in group B, none of the 8 segments responded to acetylcholine; in group C, 6 out of 8 segments responded. The contraction study showed no difference between groups A and D or between B and C. The mode of action of AS 18 antisense of c-myb is non specific but due to the presence of 4 consecutive guanosines in the oligonucleotide. Oligonucleotide with this sequence inhibits myo-intimal hyperplasia and improves endothelium-dependent relaxation in this model without affecting the contraction.