Published Online
on September 16, 2002

A more recent version of this article appeared on October 8, 2002

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Submitted on May 6, 2002
Revised on July 8, 2002
Accepted on July 8, 2002

Adenovirus-Mediated Extracellular Superoxide Dismutase Gene Therapy Reduces Neointima Formation in Balloon-Denuded Rabbit Aorta

Mikko O. Laukkanen PhD, Antti Kivelä MD, Tuomas Rissanen BM, Juha Rutanen BM, Minna K. Karkkainen MSc, Olli Leppanen MD, Jan Hinrich Bräsen MD, PhD, and Seppo Yla-Herttuala MD, PhD, FESC^*

From the A.I. Virtanen Institute (M.O.L., A.K., T.R., J.R., M.K.K., O.L., S.Y.-H.) and the Department of Medicine and Gene Therapy Unit, University of Kuopio, Kuopio, Finland (A.K., S.Y.-H.), and the HELIOS Klinikum-Berlin, Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University, Berlin, Germany (J.H.B.).

^* To whom correspondence should be addressed. E-mail: Seppo.YlaHerttuala{at}uku.fi.

Background—Restenosis is a frequent problem after invasive treatment of atherosclerotic vessels and is associated with intimal hyperplasia, which is primarily a result of proliferation and migration of smooth muscle cells, leading to the formation of neointima. Because there is no effective conventional medication for restenosis, gene therapy is a potential new treatment to prevent neointima formation.

Methods and Results—In the present study, we analyzed the effects of adenovirus-mediated extracellular superoxide dismutase (EC-SOD) gene transfer (3x10⁹ pfu/kg AdEC-SOD versus AdLacZ control virus) on neointima formation in balloon-denuded rabbit aortas. Local catheter-mediated gene transfer to the arterial wall reduced restenosis (P<0.001) and decreased the number of macrophages in the transduced segment (P<0.001) 2 weeks and 4 weeks after the gene transfer compared with AdLacZ controls. Transgene expression was detected in the arterial wall by RT-PCR 2 weeks after the procedure, and the production of superoxide anion was reduced after the gene transfer. Recovery of the endothelial layer was enhanced in EC-SOD-transduced rabbits compared with LacZ controls (P<0.001) 2 weeks after the gene transfer. The therapeutic effect was found to be extended, affecting the gene transfer site and flanking aortic segments from the renal arteries to the bifurcation. However, systemic AdEC-SOD gene transfer to liver did not have any effects on restenosis.

Conclusions—The results suggest that EC-SOD gene transfer reduces restenosis and may be useful for the prevention of intimal hyperplasia after vascular manipulations.

Key words: angioplasty • restenosis • oxygen stress • antioxidant • endothelium

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