Potential role of heme metabolism in the inducible expression of heme oxygenase-1

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 7; pp. 1813 - 1824
• Main Authors: Takeda, Taka-aki, Sasai, Machiko, Adachi, Yuka, Ohnishi, Keiko, Fujisawa, Jun-ichi, Izawa, Shingo, Taketani, Shigeru
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2017
• Subjects: aminolevulinic acid; animals; Arsenites - pharmacology; Bach1; Basic-Leucine Zipper Transcription Factors - physiology; bilirubin; biosynthesis; carbon monoxide; Carbon Monoxide - physiology; CORM3; Enzyme Induction; Fanconi Anemia Complementation Group Proteins - physiology; heavy metals; HEK293 Cells; HeLa Cells; heme; Heme - metabolism; heme oxygenase (biliverdin-producing); Heme Oxygenase-1 - biosynthesis; Heme Oxygenase-1 - genetics; Heptanoates - pharmacology; HO-1; homeostasis; HRI; Humans; iron; Isothiocyanates - pharmacology; messenger RNA; oxidative stress; protoporphyrin; Protoporphyrins - pharmacology; repressor proteins; sodium; Sodium Compounds - pharmacology; Sulforaphane; transcription (genetics); translation (genetics); ALAS1; FECH; CMH2DCFDA; HO; HO-1; MTT; DFO; SA; DMEM; BSA; CHIP; Sulforaphane; SnPP; PBS; Bach1; MARE; CoPP; PVDF; N-MePP; eIF2α; SDS-PAGE; NAC; Heme metabolism; ALA; FCS; ROS; CORM3; HRI; ZnPP
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2017.03.018

The degradation of heme significantly contributes to cytoprotective effects against oxidative stress and inflammation. The enzyme heme oxygenase-1 (HO-1), involved in the degradation of heme, forms carbon monoxide (CO), ferrous iron, and bilirubin in conjunction with biliverdin reductase, and is induced by various stimuli including oxidative stress and heavy metals. We examined the involvement of heme metabolism in the induction of HO-1 by the inducers sulforaphane and sodium arsenite. We examined the expression of HO-1 in sulforaphane-, sodium arsenite- and CORM3-treated HEK293T cells, by measuring the transcriptional activity and levels of mRNA and protein. The blockade of heme biosynthesis by succinylacetone and N-methyl protoporphyrin, which are inhibitors of heme biosynthesis, markedly decreased the induction of HO-1. The knockdown of the first enzyme in the biosynthesis of heme, 5-aminolevulinic acid synthase, also decreased the induction of HO-1. The cessation of HO-1 induction occurred at the transcriptional and translational levels, and was mediated by the activation of the heme-binding transcriptional repressor Bach1 and translational factor HRI. CO appeared to improve the expression of HO-1 at the transcriptional and translational levels. We demonstrated the importance of heme metabolism in the stress-inducible expression of HO-1, and also that heme and its degradation products are protective factors for self-defense responses. The key role of heme metabolism in the stress-inducible expression of HO-1 may promote further studies on heme and its degradation products as protective factors of cellular stresses and iron homeostasis in specialized cells, organs, and whole animal systems. [Display omitted] •Blockade of heme biosynthesis cancels the stress-inducible expression of HO-1.•The suppressed expression of HO-1 is regulated at transcription, mediated by Bach1.•The suppression of HO-1 synthesis also occurs at translation, mediated by HRI.•CO enhances the expression of HO-1 at the transcriptional and translational levels.