Long-term stabilization of vein graft wall architecture and prolonged resistance to experimental atherosclerosis after E2F decoy oligonucleotide gene therapy.

Published

Journal Article

OBJECTIVE: We tested the hypothesis that a single intraoperative transfection of rabbit vein grafts with a decoy oligonucleotide that blocks cell-cycle gene transactivation by the transcription factor E2F induces long-term stable adaptation that involves medial hypertrophy and a resistance to neointimal hyperplasia and atherosclerosis. METHODS: Jugular vein to carotid artery interposition vein grafts in hypercholesterolemic rabbits were treated, using pressure-mediated delivery, with either E2F decoy oligonucleotide, scrambled oligonucleotide, or vehicle alone. E2F decoy inhibition of cell-cycle gene expression was determined by measuring proliferating cell nuclear antigen upregulation and bromodeoxyuridine incorporation in vascular smooth muscle cells. Neointimal hyperplasia and atherosclerosis were compared between groups at 6 months after operation. Wall stress was derived from the ratio of luminal radius to wall thickness. Normal rabbits exposed to 6 weeks of diet-induced hypercholesterolemia starting 6 months after operation were analyzed in the same manner. RESULTS: The E2F decoy oligonucleotide, but not scrambled oligonucleotide or vehicle alone, inhibited proliferating cell nuclear antigen expression and smooth muscle cell proliferation. Furthermore, this manipulation of cell-cycle gene expression yielded an inhibition of neointimal hyperplasia and atherosclerotic plaque formation throughout the 6 months of cholesterol feeding. In normocholesterolemic rabbits, vehicle-treated and scrambled oligonucleotide-treated vein grafts remain susceptible to diet-induced atherosclerosis as well, whereas resistance to this disease induction remained stable in genetically engineered grafts. CONCLUSION: A single intraoperative pressure-mediated delivery of E2F decoy effectively provides vein grafts with long-term resistance to neointimal hyperplasia and atherosclerosis. These findings suggest that long-term reduction in human vein graft failure rates may be feasible with this ex vivo gene therapy approach.

Full Text

Duke Authors

Cited Authors

  • Ehsan, A; Mann, MJ; Dell'Acqua, G; Dzau, VJ

Published Date

  • April 2001

Published In

Volume / Issue

  • 121 / 4

Start / End Page

  • 714 - 722

PubMed ID

  • 11279413

Pubmed Central ID

  • 11279413

International Standard Serial Number (ISSN)

  • 0022-5223

Digital Object Identifier (DOI)

  • 10.1067/mtc.2001.111204

Language

  • eng

Conference Location

  • United States