Prostacyclin Synthase Gene Transfer Modulates Cyclooxygenase-2–Derived Prostanoid Synthesis and Inhibits Neointimal Formation in Rat Balloon-Injured Arteries

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 22; no. 2; pp. 256 - 262
• Main Authors: Yamada, Michiharu, Numaguchi, Yasushi, Okumura, Kenji, Harada, Mitsunori, Naruse, Keiji, Matsui, Hideo, Ito, Takayuki, Hayakawa, Tetsuo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.02.2002; Hagerstown, MD Lippincott
• Subjects: Angioplasty, Balloon - adverse effects; Animals; Benzenesulfonates - pharmacology; Biological and medical sciences; Carotid Arteries - physiopathology; Cyclooxygenase 2; Cytochrome P-450 Enzyme System - genetics; Dinoprostone - biosynthesis; Diseases of the cardiovascular system; Gene Transfer Techniques; Genetic Therapy; Immunohistochemistry; Indomethacin - pharmacology; Intramolecular Oxidoreductases - genetics; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Male; Medical sciences; Membrane Proteins - biosynthesis; Oxazoles - pharmacology; Prostaglandin-Endoperoxide Synthases - metabolism; Prostaglandins - biosynthesis; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Rats; Rats, Sprague-Dawley; Saccharomyces cerevisiae Proteins; Tunica Intima - injuries; Tunica Intima - pathology; Tunica Intima - physiopathology; Prostaglandin-endoperoxide synthase; Intramolecular oxidoreductases; Rat; Enzyme; Pathogenesis; Rodentia; Instrumentation therapy; Cuffed tube; Instrumental dilatation; Prostaglandin-I synthase; Artery; Genetic transfer; Restenosis; Vertebrata; Isomerases; Mammalia; Treatment; Animal; Prostanoid; Intima; Complication; Oxidoreductases
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/hq0202.104123

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.