Increased gene expression after liposome-mediated arterial gene transfer associated with intimal smooth muscle cell proliferation. In vitro and in vivo findings in a rabbit model of vascular injury.
Arterial gene transfer represents a novel strategy that is potentially applicable to a variety of cardiovascular disorders. Attempts to perform arterial gene transfer using nonviral vectors have been compromised by a low transfection efficiency. We investigated the hypothesis that cellular proliferation induced by arterial injury could augment gene expression after liposome-mediated gene transfer. Nondenuded and denuded rabbit arterial strips were maintained in culture for up to 21 d, after which transfection was performed with a mixture of the plasmid encoding firefly luciferase and cationic liposomes. In non-denuded arteries, the culture interval before transfection did not affect the gene expression. In contrast, denuded arteries cultured for 3-14 d before transfection yielded 7-13-fold higher expression (vs. day 0; P < 0.005). Transfection was then performed percutaneously to the iliac arteries of live rabbits with or without antecedent angioplasty. Gene expression increased when transfection was performed 3-7 d postangioplasty (P < 0.05). Proliferative activity of neointimal cells assessed in vitro by [3H]thymidine incorporation, and in vivo by immunostaining for proliferating cell nuclear antigen, increased and declined in parallel with gene expression. These findings thus indicate that the expression of liposome-mediated arterial gene transfer may be augmented in presence of ongoing cellular proliferation.
Takeshita
S
S
Department of Medicine (Cardiology), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135.
Gal
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Leclerc
G
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Pickering
J G
JG
Riessen
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R
Weir
L
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Isner
J M
JM
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000293:injuries* / Q000378:metabolism*; D002404:Catheterization / Q000009:adverse effects*; D002455:Cell Division; D004337:Drug Carriers; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D008081:Liposomes; D008156:Luciferases / Q000096:biosynthesis*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000293:injuries / Q000378:metabolism*; D009924:Organ Culture Techniques; D010957:Plasmids / Q000008:administration & dosage; D011817:Rabbits; D014162:Transfection / Q000379:methods*
D004337:Drug Carriers; D008081:Liposomes; D008156:Luciferases