Surgical injury of rat arteries: genetic control of the remodelling process

Objectives: Remodelling and restenosis are complex biological processes responsible for bypass and percutaneous transluminal coronary angioplasty failures which are likely to affect many hundreds of genes. We evaluated the effectiveness of topically applied antisense oligonucleotides in reducing the translation of the messenger RNA for the transcription factor c-myc and in reducing stenosis. Methods: Surgery was performed under sterile conditions 60 Wistar-Kyoto male rats were anaesthetized by ketamine. The carotid arteries were isolated through a median incision in the anterior neck region. At the same point, 0.5 mm longitudinal incisions were performed. Haemostasis was obtained by an adventitial 8.0 stitch. Thirty animals were given 150 mug of c-myc antisense oligonucleotide (Group A) while the other 30 animals received 150 mug of c-myc control sense oligonucleotide (Group B). Oligo molecules were locally applied through 100 mul of 20% pluronic gel. Rats were sacrificed at 30 days; carotid arteries were explanted and stained. Qualitative histological analysis was performed in all cases; serial sections were made every 25 mu in seven consecutive rats for each group. Morphometric analysis was also performed, luminal and medial area values recorded and the ratio between the two areas calculated. Data from each animal were compared with the corresponding controlateral carotid artery and expressed as mean +/- standard deviation. Statistical comparison between the two groups was carried out by one-way ANOVA text. Results: Qualitative histological analysis showed marked remodelling with complete disarray of vessel wall, neointima accumulation and evidence of elastic fibres in the adventitia of all animals of Group B versus Group A. Morphometric analysis showed a significant reduction in the lumen area in Group A animals together with increased values of the medial area versus Group B animals. In addition, the ratio between the lumen and medial area was significantly higher in Group A than in Group B (2.61 +/- 0.18 versus 1.14 +/- 0.33, P < 0.0001). Conclusions: c-myc antisense oligonucleotides applied intraoperatively can reduce post-operative stenosis. (C) 2002 Elsevier Science B.V. All rights reserved.