Inhibition of Neointimal Formation after Stent Placement with Adenovirus-mediated Gene Transfer of I{kappa}B{alpha} in the Hypercholesterolemic Rabbit Model: Initial Results

doi:10.1148/radiol.2233011002

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Inhibition of Neointimal Formation after Stent Placement with Adenovirus-mediated Gene Transfer of I ${kappa}$ B ${alpha}$ in the Hypercholesterolemic Rabbit Model: Initial Results¹

Manfred Cejna, MD, Johannes M. Breuss, PhD, Helga Bergmeister, DVM, MD, Rainer de Martin, PhD, Zhongying Xu, MD, Mario Grgurin, MD, Udo Losert, DVM, Hanns Plenk, Jr, MD, Bernd R. Binder, MD and Johannes Lammer, MD

¹ From the Departments of Radiology, Division of Angiography and Interventional Radiology (M.C., Z.X., M.G., J.L.) and Vascular Biology and Thrombosis Research (J.M.B., R.d.M., B.R.B.), the Center of Biomedical Research (H.B., U.L.), and Bone and Biomaterials Research, Institute for Histology and Embryology (H.P.), Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Received June 6, 2001; revision requested July 20; final revision received November 9; accepted December 11. Supported in part by a Cardiovascular and Interventional Radiological Society of Europe research grant (1999), Mallinckrodt and Schering, and Boston Scientific. Address correspondence to M.C. (e-mail: manfred.cejna@univie.ac.at).

PURPOSE: To evaluate the feasibility and efficacy of the localapplication of a replication-defective adenovirus constructfor the expression of the antiinflammatory protein I ${kappa}$ B ${alpha}$ , inhibitorof nuclear factor ${kappa}$ B (NF- ${kappa}$ B), to reduce neointimal formation afterstent placement.

MATERIALS AND METHODS: Nitinol stents were implanted in theiliac arteries of hypercholesterolemic rabbits, followed byballoon dilation (30 seconds at 6 atm). Local adenovirus-mediatedtransfer of I ${kappa}$ B ${alpha}$ (3 mL of 10⁹ plaque-forming units per milliliterat 6 atm) was performed and compared with three control groups:stent alone, stent plus local delivery of phosphate-bufferedsaline (PBS) (3 mL at 6 atm), and stent plus local deliveryof control adenovirus coding for green fluorescent protein (GFP)(3 mL of 10⁹ plaque-forming units per milliliter at 6 atm).A multichannel balloon was used for local drug delivery andballoon dilation. Animals were sacrificed 1 or 4 weeks aftertreatment. Effective transfection was demonstrated with immunofluorescencestaining. Angiographic patency and luminal diameter were evaluatedat quantitative angiography. Luminal and neointimal areas weremeasured on surface-stained ground sections with methylmethacrylateembedding and the cutting-grinding technique.

RESULTS: All vessels with stents were patent at angiography.Neointimal area was negligible in all groups 1 week after stentplacement (range, 0.42–0.52 mm²; P = .44; analysis ofvariance). Neointimal formation was demonstrated in all groups4 weeks after implantation but was significantly reduced withI ${kappa}$ B ${alpha}$ treatment compared with treatment with stent alone (by 22%,from 2.80 mm² ± 0.20 to 2.28 mm² ± 0.14, P = .05),stent plus PBS (by 43%, from 3.26 mm² ± 0.25 to 2.28mm² ± 0.14, P = .005), and stent plus GFP (by 53%, from2.32 mm² ± 0.19 to 1.51 mm² ± 0.08, P < .005).

CONCLUSION: Local adenovirus-mediated I ${kappa}$ B ${alpha}$ gene transfer has thepotential to reduce intimal hyperplasia after stent placement.

Index terms: Animals • Arteriosclerosis, 9_*.721² • Experimental study • Genes and genetics • Stents and prostheses, 981.1282, 981.1286

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