Catheter-based prostacyclin synthase gene transfer prevents in-stent restenosis in rabbit atheromatous arteries.
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 microg) 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-PGF1alpha 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).


CONCLUSIONS
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.
Numaguchi
Yasushi
Y
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Okumura
Kenji
K
Harada
Mitsunori
M
Naruse
Keiji
K
Yamada
Michiharu
M
Osanai
Hiroyuki
H
Matsui
Hideo
H
Ito
Masafumi
M
Murohara
Toyoaki
T
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002404:Catheterization; D002455:Cell Division; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D042783:Endothelial Cells / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods*; D007083:Iliac Artery / Q000378:metabolism / Q000473:pathology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D008081:Liposomes; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D011817:Rabbits; D012008:Recurrence; D015607:Stents; D014162:Transfection / Q000379:methods*; D017539:Tunica Intima / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism
D008081:Liposomes; D042461:Vascular Endothelial Growth Factor A; D015121:6-Ketoprostaglandin F1 alpha; D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase