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

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Abstract

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 nondenuded 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 (Hydrogen-3)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. (J. Clin. Invest. 1994. 93:652-661.) Key words: gene expression. cellular proliferation. liposomes. transfection. luciferase

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