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

Previous studies have shown that prostacyclin (PGI₂) 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 PGH₂ derived from COX-2 after balloon injury may be converted into PGI₂ rather than PGE₂ or thromboxane (TX) A₂ 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 PGI₂ production and decreased PGE₂ production without affecting TXA₂ production, but JTE-522 inhibited this increase in PGI₂ production. In conclusion, PCS gene transfer modulated COX-2-mediated prostanoid synthesis and inhibited neointimal formation after balloon injury.