Inhibition of neointimal formation after stent placement with adenovirus-mediated gene transfer of I kappa B alpha in the hypercholesterolemic rabbit model: initial results.
OBJECTIVE
To evaluate the feasibility and efficacy of the local application of a replication-defective adenovirus construct for the expression of the antiinflammatory protein I kappa B alpha, inhibitor of nuclear factor kappa B (NF-kappa B), to reduce neointimal formation after stent placement.


METHODS
Nitinol stents were implanted in the iliac arteries of hypercholesterolemic rabbits, followed by balloon dilation (30 seconds at 6 atm). Local adenovirus-mediated transfer of I kappa B alpha (3 mL of 10(9) plaque-forming units per milliliter at 6 atm) was performed and compared with three control groups: stent alone, stent plus local delivery of phosphate-buffered saline (PBS) (3 mL at 6 atm), and stent plus local delivery of control adenovirus coding for green fluorescent protein (GFP) (3 mL of 10(9) plaque-forming units per milliliter at 6 atm). A multichannel balloon was used for local drug delivery and balloon dilation. Animals were sacrificed 1 or 4 weeks after treatment. Effective transfection was demonstrated with immunofluorescence staining. Angiographic patency and luminal diameter were evaluated at quantitative angiography. Luminal and neointimal areas were measured on surface-stained ground sections with methylmethacrylate embedding and the cutting-grinding technique.


RESULTS
All vessels with stents were patent at angiography. Neointimal area was negligible in all groups 1 week after stent placement (range, 0.42-0.52 mm(2); P =.44; analysis of variance). Neointimal formation was demonstrated in all groups 4 weeks after implantation but was significantly reduced with I kappa B alpha treatment compared with treatment with stent alone (by 22%, from 2.80 mm(2) +/- 0.20 to 2.28 mm(2) +/- 0.14, P =.05), stent plus PBS (by 43%, from 3.26 mm(2) +/- 0.25 to 2.28 mm(2) +/- 0.14, P =.005), and stent plus GFP (by 53%, from 2.32 mm(2) +/- 0.19 to 1.51 mm(2) +/- 0.08, P <.005).


CONCLUSIONS
Local adenovirus-mediated I kappa B alpha gene transfer has the potential to reduce intimal hyperplasia after stent placement.
Cejna
Manfred
M
Department of Radiology, Division of Angiography and Interventional Radiology, Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria. manfred.cejna@univie.ac.it
Breuss
Johannes M
JM
Bergmeister
Helga
H
de Martin
Rainer
R
Xu
Zhongying
Z
Grgurin
Mario
M
Losert
Udo
U
Plenk
Hanns
H
Binder
Bernd R
BR
Lammer
Johannes
J
D000256:Adenoviridae / Q000235:genetics*; D000704:Analysis of Variance; D015901:Angiography, Digital Subtraction; D000818:Animals; D001161:Arteriosclerosis / Q000000981:diagnostic imaging / Q000517:prevention & control*; D002404:Catheterization / Q000009:adverse effects; D003251:Constriction, Pathologic / Q000000981:diagnostic imaging / Q000517:prevention & control; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006937:Hypercholesterolemia / Q000628:therapy*; D006965:Hyperplasia; D020672:I-kappa B Proteins / Q000494:pharmacology*; D007083:Iliac Artery / Q000000981:diagnostic imaging / Q000293:injuries / Q000473:pathology*; D008164:Luminescent Proteins / Q000235:genetics; D011817:Rabbits; D015607:Stents / Q000009:adverse effects; D017539:Tunica Intima / Q000473:pathology*; D014654:Vascular Patency
D020672:I-kappa B Proteins; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins