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PRECLINICAL STUDY

Extracellular Superoxide Dismutase Accelerates Endothelial Recovery and Inhibits In-Stent Restenosis in Stented Atherosclerotic Watanabe Heritable Hyperlipidemic Rabbit Aorta

Jan Hinrich Bräsen, MD^_*,,1, Olli Leppänen, MD^_*,,1, Matias Inkala, MD^_*, Tommi Heikura, MSc^_*, Max Levin, MD, PhD, Fabian Ahrens, MSc^||, Juha Rutanen, MD, PhD^_*, Hubertus Pietsch, DVM^¶, David Bergqvist, MD, PhD, Anna-Liisa Levonen, MD, PhD^_*, Samar Basu, PhD, Thomas Zeller, MD, FESC^_**, Günter Klöppel, MD, Mikko O. Laukkanen, PhD and Seppo Ylä-Herttuala, MD, PhD, FESC^_*,,_*

^_* A. I. Virtanen Institute, University of Kuopio, Kuopio, Finland
Institute for Pathology, Christian Albrechts Universität, Kiel, Germany
Uppsala University, Uppsala, Sweden
Wallenberg Laboratory, Gothenburg, Sweden
^# Humboldt University, Berlin, Germany
^¶ Schering AG, Berlin, Germany
^_** Herz-Zentrum, Bad Krozingen, Germany
University of Turku, Turku, Finland
Gene Therapy Unit, Department of Medicine, University of Kuopio, Kuopio, Finland.

Manuscript received March 23, 2007; revised manuscript received August 14, 2007, accepted August 20, 2007.

^_* Reprint requests and correspondence: Dr. Seppo Ylä-Herttuala, A. I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. (Email: seppo.ylaherttuala{at}uku.fi).

Objectives: This study examined whether local gene therapy with extracellular superoxide dismutase (EC-SOD) could inhibit in-stent restenosis in atherosclerotic Watanabe heritable hyperlipidemic rabbits.

Background: Stenting causes an acute increase in superoxide anion production and oxidative stress; EC-SOD is a major component of antioxidative defense in blood vessels and has powerful cardioprotective effects in ischemic myocardium.

Methods: Endothelial denudation and stenting were done in 36 adult (15 to 18 months old) rabbits. Catheter-mediated intramural delivery of clinical good manufacturing practice-grade adenoviruses encoding rabbit EC-SOD were done simultaneously with stenting. Control animals received adenovirus-encoding nuclear-targeted β-galactosidase (AdLacZ). Circulating markers for oxidative stress (nonesterified 8-iso-prostaglandin F₂ alpha) were measured. Analysis of 6-day, 28-day, and 90-day vessel histology, radical production, oxidation-specific epitopes, and expression studies were performed.

Results: The EC-SOD treatment reduced oxidant production in stented vessels compared with control vessels. Early systemic recovery of total SOD activity was observed in the treated rabbits. The EC-SOD significantly accelerated endothelial recovery (67.4% ± 10.8% vs. 24.2.1% ± 4.6% at 6 days, p < 0.05; 89.3% ± 3.7% vs. 45.1% ± 9.6% at 28 days, p < 0.05), and the beneficial effect involved increased proliferation of regenerating endothelium. The EC-SOD group showed a 61.3% lower (p < 0.05) neointimal formation at 28 days, with a similar, albeit nonsignificant trend at 90 days (1.20 ± 0.32 mm² vs. 1.88 ± 0.24 mm², p = 0.06).

Conclusions: The results suggest a central pathogenetic role of oxidation sensitive signaling processes in endothelial recovery and developing in-stent restenosis in atherosclerotic vessels. Local therapy against oxidative stress represents a promising therapeutic strategy in stent-induced vascular injury.

Abbreviations and Acronyms   DHE = dihydroethidium   EC-SOD = extracellular superoxide dismutase   HOCl = hypochlorite   ISR = in-stent restenosis   ONOO– = peroxynitrite   PGF2 = prostaglandin F2 alpha   SMC = smooth muscle cell   SOD = superoxide dismutase   WHHL = Watanabe heritable hyperlipidemic

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