Inhibition of intimal hyperplasia after balloon injury in rat carotid artery model using cis-element 'decoy' of nuclear factor-kappaB binding site as a novel molecular strategy.
The transcription factor, NFkB, plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes involved in atherosclerosis and lesion formation after vascular injury. We hypothesized that synthetic double-stranded DNA with high affinity for NFkB may be introduced as a 'decoy' cis element to bind the transcription factor, and block gene activation, resulting in an effective therapeutic agent for treating intimal hyperplasia. In vivo transfection of NFkB decoy oligodeoxynucleotides (ODN) into balloon-injured rat carotid artery resulted in the inhibition of neointimal formation at 14 days after injury as compared with vessels transfected with scrambled ODN (P < 0.01). It is of importance to note that in the vessels transfected with NFkB decoy ODN, the expression of p53, a pro-apoptotic gene, was upregulated in neointimal area, followed by increased apoptosis at 14 days. In addition, gene expression of ICAM-1 and VCAM-1 was markedly decreased in blood vessels transfected with NFkB decoy ODN compared with scrambled ODN, whereas balloon injury induced ICAM and VCAM expression in the neointimal area. More importantly, the migration of macrophages and T-lymphocytes into the neointima and media was significantly inhibited by NFkB decoy ODN as compared with scrambled ODN. Here, we demonstrated that in vivo transfer of NFkB decoy ODN successfully inhibited neointimal formation after balloon injury, accompanied by (1) induction of apoptosis through p53 upregulation, and (2) inhibition of local inflammatory actions through the downregulation of adhesion molecules. These results suggest that decoy treatment against NFkB provides a new therapeutic strategy to inhibit neointimal hyperplasia after angioplasty.
Yoshimura
S
S
Department of Neurosurgery, Gifu University School of Medicine, Japan.
Morishita
R
R
Hayashi
K
K
Yamamoto
K
K
Nakagami
H
H
Kaneda
Y
Y
Sakai
N
N
Ogihara
T
T
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites / Q000235:genetics; D020212:Carotid Artery Injuries / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D017536:Carotid Artery, Common / Q000276:immunology; D002404:Catheterization / Q000009:adverse effects*; D015870:Gene Expression; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D006965:Hyperplasia / Q000628:therapy; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008297:Male; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000276:immunology / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1