Up-regulation of Heme Oxygenase-1 Expression by cAMP-elevating

초록

Heme oxygenase-1 (HO-1) is the inducible form of the rate-limiting enzyme of heme degradation; itregulates the cellular contents of heme. HO-1 is up-regulated by various stimuli including oxidative stress sothat it is thought to participate in general cellular defense mechanisms against oxidative stress in mammaliancells. To investigate the role of the cAMP-dependent protein kinase A (PKA) signaling pathway on nitrogenoxidative stress-induced HO-1 gene expression, RAW 264.7 cell cultures were treated with sodium nitroprus-side (SNP). SNP increased the expression of HO-1 mRNA and protein, time- and concentration-dependently.Treatment with H89, PKA inhibitor, but not LY83583, guanylate cyclase inhibitor, significantly diminished theHO-1 expression by SNP, indicating that cAMP plays a crucial role in the induction of HO-1. Incubation withcAMP-elevating agents, such as forskolin or isoproterenol resulted in up-regulation of the expression of HO-1.Forskolin-induced expression of HO-1 was inhibited by H89. Furthermore, propranolol, βadrenoceptorblocker, inhibited the isoproterenol-induced HO-1 expression, supporting the importance of cAMP in theinduction of HO-1 expression. Higenamine-S, but not higenamineR, enhanced the HO-1 expression induced bySNP. Furthermore, cellular toxicity induced by hydrogen peroxide was attenuated by the presence of SNP,which was further increased by the presence of ZnPPIX, HO-1 inhibitor. Collectively, these results stronglysuggest that up-regulation of HO-1 expression in RAW 264.7 cells involves PKA signal pathway.

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