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Received for publication November 1, 2005.
Revised January 26, 2006.
Accepted for publication January 26, 2006.
Nitric oxide (NO) is a potent inducer of heme oxygenase (HO)-1 and NO-induced HO-1 expression is dependent on the cGMP-signaling pathway. Sodium nitroprusside (SNP) produces NO and iron. However, it is unclear whether NO is exclusively responsible for induction of HO-1 by SNP in RAW 264.7 cells. We tested our hypothesis that iron may contribute more to the SNP induction of HO-1 than does NO by comparing the HO-1 protein level and the production of NO in RAW 264.7 cells treated with SNP and S-nitroso-N-acetyl-DL-penicillamine (SNAP). Although SNP induced less NO production than SNAP, SNP induced the production of more HO-1 protein than SNAP. Deferoxamine (DFO) decreased SNP- but not SNAP-induced HO-1 expression, but did not decrease the production of NO. SNP-induced HO-1 was significantly inhibited by specific PKA inhibitors or an antagonist of cAMP, but not by guanylyl cyclase inhibitors. Exogenous iron (ferric ammonium citrate or ferricyanide) and forskolin increased the level of HO-1, which was inhibited by a PKA inhibitor H89. These results indicate that iron and cAMP, but not cGMP, play crucial roles in the induction of HO-1 in RAW 264.7 cells. Moreover, DFO and inhibitors of ERK1/2 or JNK inhibited HO-1 production induced by SNP. This study illustrates that iron rather than NO from SNP contributes to HO-1 induction. Therefore, studies on the effects of SNP should consider the role of iron in some biological functions. We concluded that iron released by SNP contributes to HO-1 induction via the cAMP-PKA-MAPK pathway.
Key words:
Nitric oxide, cAMP, Protein Kinase A, MAP Kinase, Heme metabolism, Oxidative stress
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