We investigated whether NS-398, a selective inhibitor of COX-2, induces HO-1 in IL-1 beta-stimulated vascular smooth muscle cells (VSMC). NS-398 reduced the production of PGE(2) without modulation of expression of COX-2 in IL-1 beta-stimulated VSMC. NS-398 increased HO-I mRNA and protein in a dose-dependent manner, but inhibited proliferation of IL-beta-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-beta-stimulated VSMC. CORM-2, a CO-releasing molecule, but not bilirubin inhibited proliferation of IL-beta-stimulated VSMC. NS-398 inhibited proliferation of IL-beta-stimulated VSMC in a HbO(2)-sensitive manner. In conclusion, NS-398 inhibits proliferation of IL-beta-stimulated VSMC by HO-1-derived CO. Thus, NS-398 may facilitate the healing process of vessels in vascular inflammatory disorders such as atherosclerosis. (C) 2008 Elsevier Inc. All rights reserved.