[Effects of an anti-c-myb antisense oligonucleotide on myo-intimal proliferation. Specificity of action and consequences on vasoreactivity].
Several reports have shown that an 18-mere antisense oligonucleotide directed against c-myb (AS 18) inhibits the proliferation of smooth muscle. The aims of this study were to confirm the specificity of a new anti-c-myb antisense and to evaluate changes in vasoreactivity following treatment with a c-myb antisense. Five groups of rats. 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 vasoreactivity 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 differences between groups A and D or between groups B and C. The authors conclude that 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.
Castier
Y
Y
Hôpital Broussais, Paris.
Chemla
E
E
Chardigny
C
C
Nierat
J
J
Eudes
D
D
Vasseur
M A
MA
Bruneval
P
P
Carpentier
A
A
Fabiani
J N
JN
D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D002455:Cell Division / Q000187:drug effects*; D006965:Hyperplasia; D008297:Male; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000235:genetics / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020598:Proto-Oncogene Proteins c-myb; D011519:Proto-Oncogenes / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000235:genetics*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects*
D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators