Prevention of neointimal formation after angioplasty using nuclear factor-ΚB Decoy oligodeoxynucleotide-coated balloon catheter in rabbit model

Abstract

Background-Despite the advent of drug-eluting stents, restenosis after endovascular intervention is still a major limitation in the treatment of cardiovascular disease. 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. Methods and Results-For site-specific application of NFΚB decoy oligodeoxynucleotides into target vessels during angioplasty, we developed a balloon catheter-based delivery system combined with biocompatible nanoparticles as oligodeoxynucleotides carriers. To clarify the therapeutic effect at the site of neointima, balloon angioplasty of the rabbit carotid arteries was performed at 4 weeks after initial endothelial denudation. This delivery system exhibited successful transfer of fluorescence-labeled nanospheres into the neointima in short-term contact with target vessels, and fluorescence could be detected ≥1 week after angioplasty. Consistently, local application of NFΚB decoy oligodeoxynucleotides -loaded nanospheres resulted in significant inhibition of neointimal formation, associated with inhibition of NFΚB binding activity in the injured arteries. The therapeutic effects were caused by inhibition of macrophage recruitment through the suppression of monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and CC chemokine ligand 4 expression and inhibition of vascular smooth muscle cell growth via a decrease in the expression of cyclin A and proliferating cell nuclear antigen. Importantly, application of NFΚB nanospheres accelerated restoration of the endothelial cell monolayer, associated with enhanced expression of phosphorylated Bcl-2 in endothelial cells. Conclusions-A drug-coated balloon catheter using NFΚB decoy oligodeoxynucleotides significantly inhibited the development of neointimal hyperplasia in rabbits. The present study indicates the possibility of a novel therapeutic option to prevent restenosis after angioplasty.