Induction of heme oxygenase-1 as a response in sensing the signals evoked by distinct nitric oxide donors.

To gain insights into the cellular responses evoked by nitric oxide (NO), we have studied the effects of NO donors with distinct chemistries on the expression of heme oxygenase-1 mRNA by northern blot analysis. The expression levels of heme oxygenase-1 mRNA were increased significantly in DLD-1 human colorectal adenocarcinoma cells by treatment with each of three NO donors: sodium nitroprusside (SNP), S-nitroso-L-glutathione (GSNO), and 3-morpholinosydnonimine (SIN-1). A combination of SIN-1 plus SNP or GSNO additively increased heme oxygenase-1 mRNA expression, whereas synergistic induction was seen with SNP plus GSNO. The SNP-mediated induction was not affected noticeably by extracellular superoxide dismutase, catalase, or mannitol, while the induction by SIN-1 was attenuated by superoxide dismutase. Thus, the SNP-mediated induction of heme oxygenase-1 mRNA expression may be independent of reactive oxygen species, and the induction by SIN-1 is mediated partly by peroxynitrite, which is generated by immediate reaction of NO and superoxide anion. Transient transfection assays suggested that treatment with SNP, but not with GSNO or SIN-1, increased the expression of a reporter gene through a cis-acting element, including the cadmium-responsive element, of the human heme oxygenase-1 gene. These results suggest that SNP induces heme oxygenase-1 mRNA expression through a mechanism different from that for GSNO or SIN-1. We therefore propose that induction of heme oxygenase-1 represents a common cellular response in sensing the signals evoked by distinct NO donors.