title: NS398 protects cells from sodium nitroprusside-mediated cytotoxicity through enhancing HO-1 induction independent of COX-2 inhibition.
abstract: Heme oxygenase-1 (HO-1) plays a preventive role in oxidative stress. In contrast, COX-2 is involved in the pathogenesis of many inflammatory diseases, thus COX-2 inhibitor is believed to exert anti-inflammatory properties by blocking COX-2. Recently, however, salicylate the active metabolite of aspirin showed COX-independent anti-inflammatory effects through induction of HO-1. Thus, we hypothesized that HO-1 are induced as an adaptive response to sodium nitroprusside (SNP) and play a protective role against cytotoxicity. Moreover, we investigated the protective effect of NS398 known as a selective COX-2 inhibitor on SNP-mediated cytotoxicity, and whether the protective effect of NS398 is due to COX-2 inhibition or not. SNP induced cytotoxicity in a dose-dependent manner, which was enhanced by inhibition of HO-1, suggesting that HO-1 acts in an adaptive response to SNP. Interestingly, NS398 decreased SNP-mediated cytotoxicity whereas COX-2 siRNA did not. Furthermore, NS398 enhanced SNP-induced HO-1 induction even though NS398 alone failed to induce HO-1 protein expression. In addition, NS398 enhanced SNP-induced COX-2, even though NS398 effectively inhibited SNP-mediated PGE(2) production. These results demonstrate that NS398 exerts cytoprotective effects by inducing HO-1 independent of COX-2 inhibition.
authors.affiliation: Department of Pharmacology, Gyeongsang National University, Jinju, Korea.
authors.forename: Irina Tsoy
authors.initials: IT
authors.lastname: Nizamutdinova
authors.forename: Jae Heun
authors.initials: JH
authors.lastname: Lee
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D019610:Cytoprotection; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009578:Nitrobenzenes / Q000494:pharmacology*; D009599:Nitroprusside / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D008565:Membrane Proteins; D009578:Nitrobenzenes; D034741:RNA, Small Interfering; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009599:Nitroprusside; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone