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(Circulation. 2006;114:2773-2779.)
© 2006 American Heart Association, Inc.

Coronary Heart Disease

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

Kisho Ohtani, MD, PhD; Kensuke Egashira, MD, PhD; Kaku Nakano, PhD; Gang Zhao, MD; Kouta Funakoshi, MD; Yoshiko Ihara, MD; Satoshi Kimura, MD; Ryuji Tominaga, MD, PhD; Ryuichi Morishita, MD, PhD; Kenji Sunagawa, MD, PhD

From the Departments of Cardiovascular Medicine (K.O., K.E., K.N., G.Z., Y.I., K.F., K.S.) and Surgery (S.K., R.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Division of Clinical Gene Therapy, Osaka University Medical School, Osaka, Japan (R.M.).

Correspondence to Kensuke Egashira, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp

Received August 11, 2005; revision received October 10, 2006; accepted October 13, 2006.

Background— Nuclear factor-B (NF-B) plays a critical role in the vascular response to injury. However, the role of NF-B in the mechanism of in-stent restenosis remains unclear. We therefore tested the hypothesis that blockade of NF-B by stent-based delivery of a cis-element "decoy" of NF-B reduces in-stent neointimal formation.

Methods and Results— Stents were coated with a polymer containing or not containing NF-B decoy, which represented a fast-release formulation (<7 days). Bare, polymer-coated, and NF-B decoy–eluting stents were implanted in iliac arteries of hypercholesterolemic rabbits. Increased NF-B activity was noted at early stages after stenting, which was suppressed by stent-based delivery of NF-B decoy. NF-B decoy–eluting stents also reduced monocyte infiltration and monocyte chemoattractant protein-1 expression and suppressed CD14 activation on circulating leukocytes. Importantly, NF-B 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-B decoy–eluting stents. Transfection of NF-B decoy suppressed proliferation of human coronary artery smooth muscle cells in vitro. No systemic adverse effects of NF-B decoy were detected.

Conclusions— Stent-based local delivery of NF-B 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.

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