Inhibition of neointimal hyperplasia after balloon injury by cis-element 'decoy' of early growth response gene-1 in hypercholesterolemic rabbits.
Early growth response factor-1 (Egr-1) is a transcription factor that is rapidly activated after vascular injury and thus might contribute to vascular proliferation and inflammation. We hypothesized that Egr-1 might therefore be a therapeutic target against restenosis. Hypercholesterolemic rabbits were intraluminally administered synthetic DNA as a 'decoy' against Egr-1 immediately after carotid artery balloon injury. Efficient transfection was confirmed by the delivery of a fluorescence-labeled decoy. Gel mobility-shift assay showed increased Egr-1 activity after balloon injury and its prevention by Egr-1 decoy transfection in vivo. Egr-1 decoy transfection attenuated early inflammation and proliferation and later neointimal hyperplasia. In addition, Egr-1 decoy transfection reduced gene expression and protein production of Egr-1-dependent genes such as platelet-derived growth factor-B, transforming growth factor-beta1, and monocyte chemoattractant protein-1. The Egr-1 pathway has an essential role in the pathogenesis of neointimal hyperplasia after balloon injury in hypercholesterolemic rabbits. This decoy strategy is a potential practical form of therapy for human restenosis.
Ohtani
K
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Egashira
K
K
Usui
M
M
Ishibashi
M
M
Hiasa
K-I
KI
Zhao
Q
Q
Aoki
M
M
Kaneda
Y
Y
Morishita
R
R
Takeshita
A
A
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D020212:Carotid Artery Injuries / Q000473:pathology*; D016893:Carotid Stenosis / Q000473:pathology / Q000517:prevention & control*; D004247:DNA / Q000008:administration & dosage*; D004268:DNA-Binding Proteins / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006937:Hypercholesterolemia / Q000473:pathology; D006965:Hyperplasia; D023421:Models, Animal; D011817:Rabbits; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection / Q000379:methods; D017539:Tunica Intima / Q000473:pathology
D004268:DNA-Binding Proteins; D014157:Transcription Factors; D004247:DNA