Inhibitory effects of NFkappaB decoy oligodeoxynucleotides on neointimal hyperplasia in a rabbit vein graft model.
Autologous vein remains the commonly used conduit for bypass grafts; however, neointimal hyperplasia is known to be one of the major disease processes in vein graft failure. In this study, we focused on the important role of NFkappaB which controls the expression of numerous genes for various cytokines and adhesion molecules in the mechanism of graft failure. Thus, we investigated the inhibitory effect of NFkappaB decoy oligodeoxynucleotides (ODN) on vein graft failure in a rabbit hypercholesterolemic model. Jugular vein to carotid artery interposition grafts in rabbits were transfected intraoperatively with NFkappaB decoy ODN (40 micromol/l) by ex-vivo pressure-mediated transfection (300 mm Hg, 10 min). Treatment with NFkappaB decoy ODN significantly suppressed intimal hyperplasia 4 weeks after vein implantation as compared to scrambled decoy ODN, and increased medial thickness, leading to a significant reduction in intima-to-media ratio. Treatment with NFkappaB decoy ODN significantly inhibited the recruitment of macrophages and the proliferation of vascular smooth muscle cells (VSMC), while apoptosis in VSMC was significantly increased by NFkappaB decoy ODN. In addition, a study of vascular reactivity demonstrated that transfection of grafts with NFkappaB decoy ODN significantly improved endothelium-mediated vasorelaxation as compared to scrambled decoy ODN. Here, we demonstrated that inhibition of NFkappaB activation using decoy ODN inhibited the development of neointimal hyperplasia, followed by suppression of inflammatory changes and accumulation of VSMC in the neointima of rabbit vein grafts. The present study raises the possibility of a novel strategy for prevention of graft failure.
Miyake
Takashi
T
Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Aoki
Motokuni
M
Shiraya
Suguru
S
Tanemoto
Kazuo
K
Ogihara
Toshio
T
Kaneda
Yasufumi
Y
Morishita
Ryuichi
R
D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D003251:Constriction, Pathologic / Q000473:pathology*; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D006965:Hyperplasia; D007601:Jugular Veins / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000235:genetics*; D009841:Oligonucleotides / Q000737:chemistry*; D011817:Rabbits; D019737:Transplants; D017539:Tunica Intima / Q000473:pathology*; D014680:Veins / Q000473:pathology*
D016328:NF-kappa B; D009841:Oligonucleotides