Inhibition of anastomotic intimal hyperplasia using a chimeric decoy strategy against NFkappaB and E2F in a rabbit model.
OBJECTIVE
Neointimal formation remains a major limitation after arterial reconstruction. To overcome this problem, we focused on two important transcription factors, nuclear factor-kappaB (NFkappaB) and E2F. The purpose of this study was to determine the effects of simultaneous inhibition of these transcription factors on the formation of neointimal hyperplasia.


RESULTS
We employed chimeric decoy oligodeoxynucleotides (ODN) to inhibit both NFkappaB and E2F simultaneously, and examined the effects of chimeric decoy ODN on the proliferation and migration of cultured vascular cells and on the formation of neointimal hyperplasia using prosthetic graft placement in a rabbit hypercholesterolemia model. Our in vitro study demonstrated that transfection of chimeric decoy ODN inhibited platelet-derived growth factor (PDGF)-induced proliferation and migration of vascular smooth muscle cells, whereas endothelial cell proliferation was not inhibited. In an in vivo study, treatment with chimeric decoy ODN significantly inhibited proximal and distal anastomotic intimal hyperplasia, and accelerated re-endothelialization. alpha-Smooth muscle actin (alpha-SMA)-positive cell proliferation was inhibited at the anastomotic sites. Expression of PDGF-BB and PDGF receptor-beta was also suppressed by chimeric decoy ODN, resulting in a reduction of alpha-SMA-positive cell accumulation. In addition, chimeric decoy ODN treatment inhibited macrophage accumulation, which was accompanied by a reduction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 gene expression.


CONCLUSIONS
The present study demonstrates the feasibility of chimeric decoy ODN treatment for preventing neointimal formation. This strategy might be useful to improve the clinical outcome after arterial reconstruction.
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Takashi
T
Miyake
Motokuni
M
Aoki
Ryuichi
R
Morishita
D000714:Anastomosis, Surgical; D000818:Animals; D019917:Blood Vessel Prosthesis Implantation / Q000009:adverse effects*; D002340:Carotid Artery Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005240:Feasibility Studies; D015316:Genetic Therapy / Q000379:methods*; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011817:Rabbits; D014162:Transfection; D014654:Vascular Patency
D050684:E2F Transcription Factors; D016328:NF-kappa B; D009841:Oligonucleotides; D010982:Platelet-Derived Growth Factor