Stent-Based Local Delivery of Nuclear Factor-κB Decoy Attenuates In-Stent Restenosis in Hypercholesterolemic Rabbits

Background— Nuclear factor-κB (NF-κB) plays a critical role in the vascular response to injury. However, the role of NF-κB in the mechanism of in-stent restenosis remains unclear. We therefore tested the hypothesis that blockade of NF-κB by stent-based delivery of a cis-element “decoy” of NF-κB reduces in-stent neointimal formation. Methods and Results— Stents were coated with a polymer containing or not containing NF-κB decoy, which represented a fast-release formulation (<7 days). Bare, polymer-coated, and NF-κB decoy–eluting stents were implanted in iliac arteries of hypercholesterolemic rabbits. Increased NF-κB activity was noted at early stages after stenting, which was suppressed by stent-based delivery of NF-κB decoy. NF-κB decoy–eluting stents also reduced monocyte infiltration and monocyte chemoattractant protein-1 expression and suppressed CD14 activation on circulating leukocytes. Importantly, NF-κB decoy–eluting stents attenuated neointimal formation on day 28. There was no evidence of an incomplete healing process (persistent inflammation, hemorrhage, fibrin deposition, impaired endothelial regeneration) at the site of NF-κB decoy–eluting stents. Transfection of NF-κB decoy suppressed proliferation of human coronary artery smooth muscle cells in vitro. No systemic adverse effects of NF-κB decoy were detected. Conclusions— Stent-based local delivery of NF-κB decoy reduced in-stent neointimal formation with no evidence of incomplete healing. These data suggest that this strategy may be a practical and promising means for prevention of in-stent restenosis in humans.