Inhibition of carotis venous bypass graft disease by intraoperative nucleic acid-based therapy in rabbits.
BACKGROUND
Bypass graft stenosis after venous revascularisation procedures is characterised by massive neointimal and vascular smooth muscle cell proliferation triggered via endothelin-1 synthesis in the vessel wall. Decoy oligodesoxynucleotides (ODN) against the transcription factor activator protein-1 (AP-1) inhibits pre-pro-endothelin-1 expression.


METHODS
In 20 rabbits, an end-to-side jugular vein bypass to the carotid artery was performed: (group A) 8 grafts were treated with consensus AP-1 decoy ODN, (group B) 8 with mutated control ODN and (group C) 4 received no treatment. Explantation, histomorphometric and immunohistochemical evaluation was performed after 28 days.


RESULTS
Median intimal thickness of groups: (A) 28.3 microm, (B) 48.4 microm, (C) 71.1 microm. The decoy ODN-treated group showed a significant reduction of neointima formation ( P = 0.029) and a downregulation of the endothelin receptor.


CONCLUSIONS
In this model, neointima formation was reduced by local transfection with consensus decoy ODN against AP-1. Endothelin A and B receptor expression is downregulated. Molecular target nucleic acid-based therapies seem to be a future means of overcoming neointima proliferation in pressure-induced venous graft failure. Intraoperative local application makes it easy to use in routine revascularisation procedures.
Kusch
B
B
Clinic for Cardiac Surgery, University Hospital Giessen and Marburg, Position Marburg, Marburg, Germany.
Waldhans
S
S
Sattler
A
A
Wagner
A
A
Hecker
M
M
Moosdorf
R
R
Vogt
S
S
D000818:Animals; D002339:Carotid Arteries; D001026:Coronary Artery Bypass; D004195:Disease Models, Animal; D015536:Down-Regulation; D019332:Endothelin-1 / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D008297:Male; D009841:Oligonucleotides / Q000627:therapeutic use*; D011817:Rabbits; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D014162:Transfection; D017539:Tunica Intima / Q000473:pathology
D019332:Endothelin-1; D009841:Oligonucleotides; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D018808:Transcription Factor AP-1