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

AbstractOBJECTIVE:
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.
AuthorsA Ehsan, M J Mann, G Dell'Acqua, V J Dzau
JournalThe Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 121 Issue 4 Pg. 714-22 (Apr 2001) ISSN: 0022-5223 [Print] United States
PMID11279413 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antimetabolites
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cholesterol, Dietary
  • DNA Probes
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Proliferating Cell Nuclear Antigen
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • Bromodeoxyuridine
Topics
  • Anastomosis, Surgical
  • Animals
  • Antimetabolites (pharmacokinetics, therapeutic use)
  • Arteriosclerosis (chemically induced, genetics, metabolism, therapy)
  • Bromodeoxyuridine (pharmacokinetics, therapeutic use)
  • Carotid Artery Diseases (chemically induced, metabolism, pathology, prevention & control)
  • Carotid Artery, Common (surgery)
  • Carrier Proteins
  • Cell Cycle Proteins (genetics, therapeutic use)
  • Cell Division (drug effects)
  • Cholesterol, Dietary (toxicity)
  • DNA Probes (chemistry)
  • DNA-Binding Proteins
  • Disease Progression
  • E2F Transcription Factors
  • Genetic Therapy (methods)
  • Hypertrophy
  • Jugular Veins (metabolism, pathology, transplantation)
  • Muscle, Smooth, Vascular (drug effects, pathology)
  • Proliferating Cell Nuclear Antigen (drug effects, metabolism)
  • Rabbits
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors (genetics, therapeutic use)
  • Transfection
  • Tunica Intima (drug effects, pathology)
  • Up-Regulation (drug effects)

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