This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamada, M. Articles by Hayakawa, T. Search for Related Content PubMed PubMed Citation Articles by Yamada, M. Articles by Hayakawa, T. Related Collections Restenosis Gene therapy Other Vascular biology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:256.)
© 2002 American Heart Association, Inc.

Vascular Biology

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

Michiharu Yamada; Yasushi Numaguchi; Kenji Okumura; Mitsunori Harada; Keiji Naruse; Hideo Matsui; Takayuki Ito; Tetsuo Hayakawa

From Internal Medicine II (M.Y., K.O., M.H., H.M., T.H.), Physiology II (K.N.), and the Department of Health Sciences (T.I.), Nagoya University School of Medicine, Nagoya, Japan, and the Departments of Surgery and Pathology (Y.N.), Children’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Kenji Okumura, MD, Internal Medicine II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. E-mail kenji{at}med.nagoya-u.ac.jp

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.

Key Words: prostacyclin • cyclooxygenase-2 • gene therapy • restenosis • balloon injury

This article has been cited by other articles:

				A. Hirao, K. Kondo, K. Takeuchi, N. Inui, K. Umemura, K. Ohashi, and H. Watanabe Cyclooxygenase-dependent vasoconstricting factor(s) in remodelled rat femoral arteries Cardiovasc Res, July 1, 2008; 79(1): 161 - 168. [Abstract] [Full Text] [PDF]

				A. V. R. Santhanam, L. A. Smith, T. He, K. A. Nath, and Z. S. Katusic Endothelial Progenitor Cells Stimulate Cerebrovascular Production of Prostacyclin By Paracrine Activation of Cyclooxygenase-2 Circ. Res., May 11, 2007; 100(9): 1379 - 1388. [Abstract] [Full Text] [PDF]

				K. Yokouchi, Y. Numaguchi, R. Kubota, M. Ishii, H. Imai, R. Murakami, Y. Ogawa, T. Kondo, K. Okumura, D. E. Ingber, et al. l-Caldesmon Regulates Proliferation and Migration of Vascular Smooth Muscle Cells and Inhibits Neointimal Formation After Angioplasty Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2231 - 2237. [Abstract] [Full Text] [PDF]

				Y. Numaguchi, K. Okumura, M. Harada, K. Naruse, M. Yamada, H. Osanai, H. Matsui, M. Ito, and T. Murohara Catheter-based prostacyclin synthase gene transfer prevents in-stent restenosis in rabbit atheromatous arteries Cardiovasc Res, January 1, 2004; 61(1): 177 - 185. [Abstract] [Full Text] [PDF]

				J. A. Ospina, S. P. Duckles, and D. N. Krause 17{beta}-Estradiol decreases vascular tone in cerebral arteries by shifting COX-dependent vasoconstriction to vasodilation Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H241 - H250. [Abstract] [Full Text] [PDF]

				O. Belton and D. Fitzgerald Cyclooxygenase-2 inhibitors and atherosclerosis J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1820 - 1822. [Full Text] [PDF]