Administration of a decoy against the activator protein-1 binding site suppresses neointimal thickening in rabbit balloon-injured arteries

Circulation. 2002 Mar 12;105(10):1226-32. doi: 10.1161/hc1002.104903.

Abstract

Background: Transcription factor activator protein-1 (AP-1) is activated and upregulated in injured arterial smooth muscle cells in vivo, yet the exact role of the AP-1--related pathway in vascular disease in vivo has remained unclear. We examined the role of the transfer of synthetic double-stranded cis-element decoy oligodeoxynucleotides (ODNs) in balloon-injured rabbit carotid arteries and the effects of these ODNs on neointimal thickening.

Methods and results: Transfection of fluorescein isothiocyanate--labeled ODNs using the hemagglutinating virus of Japan liposome method resulted in widespread distribution of fluorescent nuclear signals over the entire medial layer in injured arteries. Gel mobility shift assay revealed that AP-1 DNA binding was activated and that the AP-1 decoy reduced AP-1 DNA binding activity as a result of specific binding affinity to AP-1 in vivo. In morphometric analyses, AP-1 decoy led to a significant reduction in the neointimal area and a significant reduction in cell number and transforming growth factor-beta(1) production of human aortic smooth muscle cells under conditions of platelet-derived growth factor stimulation.

Conclusions: Because AP-1 decoy transfection in vivo dramatically prevented neointimal thickening in balloon-injured arteries, AP-1 may be a useful molecular target for gene therapy to reduce restenosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Binding Sites / drug effects
  • Binding, Competitive / drug effects
  • Carotid Artery Injuries*
  • Carotid Artery, Common / pathology
  • Carotid Stenosis / etiology
  • Carotid Stenosis / pathology
  • Carotid Stenosis / prevention & control*
  • Catheterization / adverse effects
  • Cell Count
  • Cell Division / drug effects
  • Cells, Cultured
  • DNA / metabolism
  • Disease Models, Animal
  • Fluorescein-5-isothiocyanate
  • Genetic Therapy / methods*
  • Humans
  • Liposomes
  • Male
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Oligonucleotides / genetics
  • Oligonucleotides / metabolism
  • Oligonucleotides / pharmacology*
  • Rabbits
  • Sendai virus / genetics
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factor AP-1 / metabolism*
  • Transfection
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1
  • Tunica Intima / drug effects*
  • Tunica Intima / injuries
  • Tunica Intima / metabolism

Substances

  • Liposomes
  • Oligonucleotides
  • TGFB1 protein, human
  • Transcription Factor AP-1
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • DNA
  • Fluorescein-5-isothiocyanate