Extracellular superoxide dismutase accelerates endothelial recovery and inhibits in-stent restenosis in stented atherosclerotic Watanabe heritable hyperlipidemic rabbit aorta.
OBJECTIVE
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 beta-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.
A. I. Virtanen Institute, University of Kuopio, Kuopio, Finland.
Jan Hinrich
JH
Bräsen
Olli
O
Leppänen
Matias
M
Inkala
Tommi
T
Heikura
Max
M
Levin
Fabian
F
Ahrens
Juha
J
Rutanen
Hubertus
H
Pietsch
David
D
Bergqvist
Anna-Liisa
AL
Levonen
Samar
S
Basu
Thomas
T
Zeller
Günter
G
Klöppel
Mikko O
MO
Laukkanen
Seppo
S
Ylä-Herttuala
D000256:Adenoviridae; D000818:Animals; D001018:Aortic Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D005822:Genetic Vectors; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D018384:Oxidative Stress / Q000502:physiology; D011817:Rabbits; D015607:Stents / Q000009:adverse effects*; D013482:Superoxide Dismutase / Q000008:administration & dosage*
D016166:Free Radical Scavengers; D013482:Superoxide Dismutase