Effect of transfer of synthetic double-stranded cis-element "decoy" oligodeoxynucleotides(ODNs) on neointimal thickening.

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Background--Progressive neointimal thickening and restenosis remain major critical problems limiting the long-term efficacy of percutaneous transluminal coronary angioplasty or bypass surgery to treat subjects with vascular occlusive diseases. We examined the role of transfer of synthetic double-stranded cis-element "decoy" oligodeoxynucleotides(ODNs) in case of balloon injured rabbit carotid arteries and effects of these ODNs on neointimal thickening were investigated.Methods and Results--Transfection of flurescein isothiocyante(FITC)-labeled ODNs, using the hemagglutinating virus of Japan(HVJ)-liposome method, resulted in widespread distribution of fluorescent nuclear signals over the entire medial layer, while direct transfer of unmodified FITC-labeled ODNs showed patchy and scattered distribution in balloon injured rabbit carotid arteries. The gel mobility shift revealed that AP-1 DNA binding was activated, and that the AP-1 decoy ODNs reduced AP-1 DNA binding activity, as a result of specific binding affinity to AP-1 in vivo. In morphometric analyses, AP-1 decoy ODNs led to a significant reduction in the neointimal area and a significant reduction in cell number of human aortic smooth muscle cells, under conditions of platelet-derived growth factor stimulation.Conclusions--As AP-1 decoy ODNs transfection in vivo dramatically prevented neointimal thickening in balloon injured arteries, AP-1 may be an useful molecular target for gene therapy to reduce restenosis.