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Extracellular superoxide dismutase accelerates endothelial recovery and inhibits in-stent restenosis in stented atherosclerotic Watanabe heritable hyperlipidemic rabbit aorta
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Vascular surgery)
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2007 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 50, no 23, 2249-2253 p.Article in journal (Refereed) Published
Abstract [en]

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.

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

Jan Hinrich Bräsen, Olli Leppänen, Matias Inkala, Tommi Heikura, Max Levin, Fabian Ahrens, Juha Rutanen, Hubertus Pietsch, David Bergqvist, Anna-Liisa Levonen, Samar Basu, Thomas Zeller, Günter Klöppel, Mikko O. Laukkanen, Seppo Ylä-Herttuala

Percutaneous coronary interventions induce oxidative stress in vessels that already have compromised antioxidative defenses. Extracellular superoxide dismutase (EC-SOD) is a major antioxidant in healthy arteries, and exogenous EC-SOD confers powerful vasculoprotective and cardioprotective effects. However, the effects of EC-SOD therapy on stent-induced vascular injury have not been assessed. We present evidence showing that local therapy with EC-SOD, delivered using clinical-grade adenoviruses, attenuated tissue oxidant production, suppressed developing in-stent restenosis, and accelerated endothelial recovery.

Place, publisher, year, edition, pages
2007. Vol. 50, no 23, 2249-2253 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-12550DOI: 10.1016/j.jacc.2007.08.038ISI: 000251330800010PubMedID: 18061074OAI: oai:DiVA.org:uu-12550DiVA: diva2:40319
Available from: 2008-05-31 Created: 2008-05-31 Last updated: 2017-12-11Bibliographically approved

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Bergqvist, DavidBasu, Samar

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