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

Abstract

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 (Ͻ7 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.

ALOX5AP variants are associated with in-stent restenosis after percutaneous coronary intervention

“…Although the leukotriene pathway has not been previously implicated in in-stent restenosis pathophysiology, inflammation is known to play an important role. Targeting inflammatory pathways may have utility in preventing in-stent restenosis 19 , and pharmacologic agents targeting the leukotriene pathway are available. Tranilast, an antiasthma drug that inhibits leukotriene C 4 release from mast cells and macrophages 20 , and interferes with proliferation and migration of vascular SMCs 21 , has been shown to reduce neointimal thickening after vascular injury in animal models 22 .…”

Pitavastatin-Incorporated Nanoparticle-Eluting Stents Attenuate In-Stent Stenosis without Delayed Endothelial Healing Effects in a Porcine Coronary Artery Model

“…We previously reported the central role of monocyte-mediated inflammation in the pathogenesis of instent neointima formation [28][29][30][31] and the formulation of polymeric gene-eluting stents or nuclear factor kappa-B decoy, inhibiting in-stent stenosis 28,32) ; however, although advanced polymer technology was used, we were not able to formulate appropriate statin coating on metallic stents (authors' unpublished observation). An important finding of this study is that pitavastatin-NP-eluting stents attenuated in-stent stenosis (neointima formation) as effectively as sirolimus-eluting sue factor expression ( Fig.…”

Nanoparticle-Mediated Delivery of Pitavastatin Into Lungs Ameliorates the Development and Induces Regression of Monocrotaline-Induced Pulmonary Artery Hypertension

“…The ␣-p65 monoclonal antibody recognizes an epitope on the p65 subunit that is masked by bound inhibitor-B. 19 Therefore, this antibody exclusively detects activated NF-B. 19 …”

“…12,19 TaqMan primers/probes for monocyte chemotactic protein-1, tumor necrosis factor-␣, interleukin (IL)-1␤, IL-6, intercellular adhesion molecule-1, and glyceraldehyde 3-phosphate dehydrogenase, which served as the endogenous reference, were purchased from Applied Biosystems (Assay-on-Demand gene expression products Rn00580555, Rn99999017, Rn00580432, Rn00561420, and Rn00564227 and TaqMan rodent glyceraldehyde 3-phosphate dehydrogenase control reagents, respectively).…”