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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:727-733.)
© 1999 American Heart Association, Inc.

Original Contributions

Prostacyclin Synthase Gene Transfer Accelerates Reendothelialization and Inhibits Neointimal Formation in Rat Carotid Arteries After Balloon Injury

Yasushi Numaguchi; Keiji Naruse; Mitsunori Harada; Hiroyuki Osanai; Shinji Mokuno; Kichiro Murase; Hideo Matsui; Yukio Toki; Takayuki Ito; Kenji Okumura; Tetsuo Hayakawa

From the Department of Internal Medicine II (Y.N., M.H., H.O., S.M., K.M., H.M., Y.T., K.O., T.H.) and Physiology (K.N.), Nagoya University School of Medicine, and Nagoya University School of Health Science (T.I.), Department of Internal Medicine II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Correspondence to Yasushi Numaguchi, Department of Internal Medicine II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. E-mail numa2{at}tsuru.med.nagoya-u.ac.jp

Abstract—Prostacyclin (PGI₂), a metabolite of arachidonic acid, has the vasoprotective effects of vasodilation, anti-platelet aggregation, and inhibition of smooth muscle cell proliferation. We hypothesized that an overexpression of endogenous PGI₂ may accelerate the recovery from endothelial damage and inhibit neointimal formation in the injured artery. To test this hypothesis, we investigated in vivo transfer of the PGI₂ synthase (PCS) gene into balloon-injured rat carotid arteries by a nonviral lipotransfection method. Seven days after transfection, a significant regeneration of endothelium was observed in the arteries transfected with a plasmid carrying the rat PCS gene (pCMV-PCS), but little regeneration was seen in those with the control plasmid carrying the lacZ gene (pCMV-lacZ) (percent luminal circumference lined by newly regenerated endothelium: 87.1±6.9% in pCMV-PCS-transfected vessels and 6.9±0.2% in pCMV-lacZ vessels, P<0.001). BrdU staining of arterial segments demonstrated a significantly lower incorporation in pCMV-PCS-transfected vessels (7.5±0.3% positive nuclei in vessel cells) than in pCMV-lacZ (50.7±9.6%, P<0.01). Moreover, 2 weeks after transfection, the PCS gene transfer resulted in a significant inhibition of neointimal formation (88% reduction in ratio of intima/media areas), whereas medial area was similar among the groups. Arterial segments transfected with pCMV-PCS produced significantly higher levels of 6-keto-PGF₁, the main metabolite of PGI₂, compared with the segments transfected with pCMV-lacZ (10.2±0.55 and 2.1±0.32 ng/mg tissue for pCMV-PCS and pCMV-placZ, P<0.001). In conclusion, this study demonstrated that an in vivo PCS gene transfer increased the production of PGI₂ and markedly inhibited neointimal formation with accelerated reendothelialization in rat carotid arteries after balloon injury.

Key Words: prostacyclin • prostacyclin synthase • restenosis • gene therapy • balloon injury

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