Prostacyclin synthase gene transfer modulates cyclooxygenase-2-derived prostanoid synthesis and inhibits neointimal formation in rat balloon-injured arteries.

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Abstract
Previous studies have shown that prostacyclin (PGI 2 ) synthase (PCS) gene transfer inhibits neointimal formation in balloon-injured arteries. However, the role of each cyclooxygenase (COX) isoform in this healing mechanism remains unknown. We hypothesized that overexpression of PCS may modulate COX-2–mediated prostaglandin (PG) metabolism. That is to say, excessive PGH 2 derived from COX-2 after balloon injury may be converted into PGI 2 rather than PGE 2 or thromboxane (TX) A 2 by overexpressed PCS. We examined the expression of COX isoforms and evaluated the role of COX-2 with regard to the effects of PCS gene transfer by using 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide (JTE-522), a selective COX-2 inhibitor. Rats were divided into 4 groups in conjunction with PCS gene transfer and JTE-522 treatment. The PCS gene (30 μg) was transfected into rat balloon-injured arteries by a lipotransfection method. JTE-522 (30 mg/kg per day) was administered for 14 days after balloon injury. Immunohistochemical analysis demonstrated marked COX-2 expression on the neointima. PCS gene transfer markedly inhibited neointimal formation, but JTE-522 reversed this beneficial effect. PCS gene transfer augmented PGI 2 production and decreased PGE 2 production without affecting TXA 2 production, but JTE-522 inhibited this increase in PGI 2 production. In conclusion, PCS gene transfer modulated COX-2–mediated prostanoid synthesis and inhibited neointimal formation after balloon injury.

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