Inhibition of Carotis Venous Bypass Graft Disease by Intraoperative Nucleic Acid-Based Therapy in Rabbits

Abstract

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 µm, (B) 48.4 µm, (C) 71.1 µm. 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.

Key words

CABG - venous grafts - venous disease - atherosclerosis - gene therapy - animal model

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