NS-398, a selective COX-2 inhibitor, inhibits proliferation of IL-1beta-stimulated vascular smooth muscle cells by induction of HO-1.
We investigated whether NS-398, a selective inhibitor of COX-2, induces HO-1 in IL-1beta-stimulated vascular smooth muscle cells (VSMC). NS-398 reduced the production of PGE(2) without modulation of expression of COX-2 in IL-1beta-stimulated VSMC. NS-398 increased HO-1 mRNA and protein in a dose-dependent manner, but inhibited proliferation of IL-1beta-stimulated VSMC. Furthermore, SnPPIX, a HO-1 inhibitor, reversed the effects of NS-398 on PGE(2) production, suggesting that COX-2 activity can be affected by HO-1. Hemin, a HO-1 inducer, also reduced the production of PGE(2) and proliferation of IL-1beta-stimulated VSMC. CORM-2, a CO-releasing molecule, but not bilirubin inhibited proliferation of IL-1beta-stimulated VSMC. NS-398 inhibited proliferation of IL-1beta-stimulated VSMC in a HbO(2)-sensitive manner. In conclusion, NS-398 inhibits proliferation of IL-1beta-stimulated VSMC by HO-1-derived CO. Thus, NS-398 may facilitate the healing process of vessels in vascular inflammatory disorders such as atherosclerosis.
Choi
Hyoung Chul
HC
Department of Pharmacology and Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717, Republic of Korea.
Kim
Hee Sun
HS
Lee
Kwang Youn
KY
Chang
Ki Churl
KC
Kang
Young Jin
YJ
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D009578:Nitrobenzenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051547:Heme Oxygenase-1; D015232:Dinoprostone