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Cardiovascular Research 1999 43(2):481-491; doi:10.1016/S0008-6363(99)00107-8
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Prostacyclin synthase gene transfer inhibits neointimal formation in rat balloon-injured arteries without bleeding complications

Mitsunori Haradaa,*, Yukio Tokia, Yasushi Numaguchia, Hiroyuki Osanaia, Takayuki Itob, Kenji Okumuraa and Tetsuo Hayakawaa

aInternal Medicine II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
bDepartment of Health Sciences, Nagoya University School of Medicine, 1-1-20 Daikominami Higashi-ku, Nagoya 461-8673, Japan

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

Objective: This study was designed to compare the effects of prostacyclin synthase (PCS) gene transfer with those of a systemic infusion of beraprost sodium (BPS), a prostacyclin analogue, on vascular smooth muscle cell (VSMC) proliferation and neointimal formation after arterial injury. Methods: PCS gene (3 or 30 µg) was transfected into rat balloon-injured carotid arteries by a non-viral lipotransfection method. BPS (100 or 300 µg/kg/day) was subcutaneously infused with osmotic pumps after the injury. LacZ gene (30 µg) was used as a control. VSMC proliferation was estimated by the bromodeoxyuridine (BrdU) index (BrdU-positive nuclei/total nuclei) at day 7. Neointimal formation was evaluated at day 14. Each treatment group had six rats. Results: PCS gene transfer prevented the increase in intimal/medial area ratio (3 µg: 46.6%, 30 µg: 61.1% reduction; P<0.05, P<0.01, respectively), as did BPS 300 µg/kg/day (49.8% reduction; P<0.05). BPS 100 µg/kg/day, however, had no effects on the ratio. PCS gene transfer and BPS 300 µg/kg/day significantly suppressed the BrdU index. BPS 300 µg/kg/day group had more frequent hematoma and longer bleeding time. There were no significant differences in blood pressure, heart rate, or urinary volume among all groups. Conclusion: Both PCS gene transfer and BPS 300 µg/kg/day reduced neointimal formation after arterial injury by inhibiting VSMC proliferation. PCS gene transfer may be a safer therapeutic modality against neointimal formation than a systemic infusion of BPS because the former method resulted in fewer bleeding complications.

KEYWORDS Arteries; Gene therapy; Hemostasis; Prostaglandins; Restenosis; Rat


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