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Cardiovascular Research 2004 61(1):177-185; doi:10.1016/j.cardiores.2003.10.016
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Catheter-based prostacyclin synthase gene transfer prevents in-stent restenosis in rabbit atheromatous arteries

Yasushi Numaguchia, Kenji Okumura*,a, Mitsunori Haradaa, Keiji Naruseb, Michiharu Yamadaa, Hiroyuki Osanaia, Hideo Matsuia, Masafumi Itoc and Toyoaki Muroharaa

aDepartments of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
bDepartments of Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
cDepartments of Pathology, Nagoya University Hospital, Nagoya, Japan

* Corresponding author. Tel.: +81-52-744-2168; fax: +81-52-744-2175. kenji{at}med.nagoya-u.ac.jp

Objective: Prostacyclin synthase (PGIS) gene transfer have been shown to accelerate re-endothelialization and prevent neointimal formation in balloon-injured arteries. The aim of this study is to evaluate how overexpression of endogenous prostacyclin exerts those beneficial effects in atheromatous arteries. Methods: New Zealand White Rabbits fed a 0.5% cholesterol diet underwent balloon injury and Palmaz–Schatz stent implantation in the iliac arteries followed PGIS gene (pCMV-PGIS, 200 µg) delivery by the lipotransfection method via Dispatch catheter (n = 6 each). Results: One week after transfection, arterial segments of pCMV-PGIS produced higher levels of 6-keto-PGF1{alpha} than those of control, pCMV-LacZ (p<0.05). The levels of vascular endothelial growth factor (VEGF) expression was greater in the vessels of pCMV-PGIS than in those of pCMV-LacZ demonstrated by immunohistochemical analysis and quantitation of Western blotting (1.8-fold, p<0.05). At 2 weeks, in-stent endothelialization was significantly greater in the vessels of pCMV-PGIS than in those of pCMV-LacZ (p<0.01). The percentage of BrdU-positive nuclei in the injured arterial segments was lower in vessels of pCMV-PGIS than pCMV-LacZ (p<0.01). At 4 weeks, PGIS gene transfer reduced the neointimal area by 38% (p<0.05) and widened the lumen area by 71% (p<0.01). Conclusion: PGIS gene transfer accelerated re-endothelialization, and attenuated neointimal formation after stent implantation in atheromatous rabbit arteries, at least in part, via increased production of VEGF protein.

KEYWORDS Atherosclerosis; Gene therapy; Prostaglandins; Restenosis; Stents

Time for primary review 35 days


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