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KMID : 0043320090320010099
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Archives of Pharmacal Research
2009 Volume.32 No. 1 p.99 ~ p.107
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NS398 Protects Cells from Sodium Nitroprusside-mediated Cytotoxicity through Enhancing HO-1 Induction Independent of COX-2 Inhibition
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Kim Hye-Jung
Seo Han-Geuk
Chang Ki-Churl
Nizamutdinova Irina Tsoy
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Abstract
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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 PGE2 production. These results demonstrate that NS398 exerts cytoprotective effects by inducing HO-1 independent of COX-2 inhibition.
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KEYWORD
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HO-1, COX-2, SNP, NS398, Adaptive response
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