Published Online
on November 27, 2006

A more recent version of this article appeared on December 19, 2006

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Submitted on August 11, 2005
Revised on October 10, 2006
Accepted on October 13, 2006

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, and 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.).

^* To whom correspondence should be addressed. E-mail: egashira{at}cardiol.med.kyushu-u.ac.jp.

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.

Key words: inflammation • monocytes • restenosis • myocytes, smooth muscle

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