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.
Subject(s)
Angioplasty, Balloon/instrumentation , Carotid Artery Injuries/therapy , Coated Materials, Biocompatible , Coronary Vessels/metabolism , NF-kappa B/metabolism , Neointima , Oligodeoxyribonucleotides/administration & dosage , Vascular Access Devices , Angioplasty, Balloon/adverse effects , Animals , Carotid Artery Injuries/diagnosis , Carotid Artery Injuries/etiology , Carotid Artery Injuries/genetics , Carotid Artery Injuries/metabolism , Constriction, Pathologic , Coronary Vessels/pathology , Disease Models, Animal , Gene Expression Regulation , Male , NF-kappa B/genetics , Nanoparticles , Rabbits , Signal Transduction , Time FactorsABSTRACT
RATIONALE AND OBJECTIVES: Whether the degree of diffuse hepatic damage is correlated with the signal change on MR images after injection of superparamagnetic iron oxide (SPIO) particles was investigated. In addition, we investigated whether hepatic function deteriorates after injection of SPIO. METHODS: Seventy-six female Sprague-Dawley rats aged 3 to 4 weeks were given drinking water containing 0.03% thioacetamide (TAA) for 4 or 12 weeks to induce two grades of liver injury. Seventeen normal rats were served as a control. Normal and model rats were administered Resovist (10 micromol Fe/kg), and signal intensities in the liver on MR images obtained at 4.7 T were measured up to 60 minutes after injection (n = 5). The model rats were injected with 10 times the envisaged dose of Resovist (100 micromol Fe/kg) or saline as a control substance, and blood parameters were measured at 4, 24, and 48 hours after injection (n = 5 or 6). At 4 hours after injection, iron and Kupffer cells in the liver were stained (n = 3). RESULTS: Maximal signal reduction in the liver occurred 15 minutes after injection in all groups. The reduced signal persisted for 60 minutes after injection. However, the degree of maximal signal reduction in the model rats was significantly less than that in the normal rats (P < 0.05, 0.01). Signal reduction in the 12-week group was less than that in the 4-week group. In control rats, the number of iron-positive cells increased by 22 cells per area (0.065 mm(2)) following treatment with Resovist. In the 4-week and 12-week groups, numbers of iron-positive cells increased by 13 and 11 cells, respectively. There was no statistically significant difference in the number of Kupffer cells between control and model rats. No significant change was observed in blood parameters with Resovist. CONCLUSION: The MR signal induced by Resovist depended on the degree of phagocytic activity in the liver. The safety profiles of Resovist remained unchanged even at 10 times the imaging dose.
