Abstract 15371: Prevention of Neointimal Formation After Angioplasty Using NF-kappaB Decoy Oligodeoxynucleotide-Coated Balloon Catheter in Rabbit Restenosis Model
Despite the potent inhibitory effect of drug-eluting stents on restenosis after endovascular intervention, there is still a major concern regarding their association with incomplete vascular healing. To regulate the multiple biological mechanisms underlying restenosis, we focused on inhibition of an important transcription factor, nuclear factor-kappaB (NFκB), using a decoy strategy. For application of NFκB decoy oligodeoxynucleotides (ODN) into target vessels during angioplasty, we developed a catheter based site-specific delivery system using a chitosan-modified PLGA nanosphere-coated balloon. In this study, we evaluated the effects of local application of NFκB decoy ODN-loaded nanospheres (NFκB-NS) on neointimal formation after angioplasty in two types of rabbit vascular injury models. To clarify the therapeutic effect at the site of neointima, balloon angioplasty of the carotid arteries was performed at four weeks after initial endothelial denudation. This delivery system exhibited successful transfer of fluorescence-labeled nanoparticles into the neointima of the carotid artery, and fluorescence could be detected at least three weeks after angioplasty. Consistently, local application of NFκB-NS resulted in significant inhibition of neointimal formation (n=11, p<0.05), associated with inhibition of NFκB binding activity in the injured arteries. The therapeutic effects were due to inhibition of macrophage recruitment through the suppression of MCP-1 and VCAM-1 gene expression (n=5, p<0.05), and inhibition of VSMC growth via a decrease in the expression of cyclin A and proliferating cell nuclear antigen (n=5, p<0.05). Importantly, local application of NFκB-NS significantly accelerated restoration of the endothelial cell monolayer, associated with enhanced expression of phosphorylated Bcl-2 in endothelial cells (n=5, p<0.05). Here, a drug-coated balloon catheter using NFκB decoy ODN significantly inhibited the development of neointimal hyperplasia in rabbit models. The present study indicates the possibility of a novel therapeutic option to prevent restenosis after angioplasty.
- © 2012 by American Heart Association, Inc.