Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Up-regulation of Heme Oxygenase-1 Expression by cAMP-elevating Agents in RAW 264.7 cells

  • Ko, Young-Shin (Department of pharmacology, College of Medicine, Gyeongsang National University, Institute of Health Sciences) ;
  • Park, Min-Kyu (Department of pharmacology, College of Medicine, Gyeongsang National University, Institute of Health Sciences) ;
  • Kang, Young-Jin (Department of pharmacology, College of Medicine, Gyeongsang National University, Institute of Health Sciences) ;
  • Lee, Young-Soo (Department of pharmacology, College of Medicine, Gyeongsang National University, Institute of Health Sciences) ;
  • Seo, Han-Geuk (Department of pharmacology, College of Medicine, Gyeongsang National University, Institute of Health Sciences) ;
  • Lee, Duck-Hyung (Department of Chemistry, Sogang University) ;
  • Yunchoi, Hye-Sook (Natural Products Research Institute, Seoul National University) ;
  • Chong, Won-Seog (Department of pharmacology, College of Medicine, Sonam University) ;
  • Chang, Ki-Churl (Department of pharmacology, College of Medicine, Gyeongsang National University, Institute of Health Sciences)
  • Published : 2002.06.01
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Abstract

Heme oxygenase-1 (HO-1) is the inducible from of the rate-limiting enzyme of heme degradation; it regulates the cellular contents of heme. HO-1 is up-regulated by various stimuli including oxidative stress so that it is thought to participate in general cellular defense mechanisms against oxidative stress in mammalian cells. To investigate the role of the cAMP-dependent protein kinase A (PKA) signaling pathway on nitrogen oxidative stress-induced HO-1 gene expression, RAW 264.7 cell cultures were treated with sodium nitroprusside (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 the HO-1 expression by SNP, indicating that cAMP plays a crucial role in the induction of HO-1. Incubation with cAMP-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, $\beta$-adrenoceptor blocker, inhibited the isoproterenol-induced HO-1 expression, supporting the importance of cAMP in the induction of HO-1 expression. Higenamine-S, but not higenamineR, enhanced the HO-1 expression induced by SNP. 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 strongly suggest that up-regulation of HO-1 expression in RAW 264.7 cells involves PKA signal pathway.

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References

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