title: Hypoxia reduces the expression of heme oxygenase-2 in various types of human cell lines. A possible strategy for the maintenance of intracellular heme level.
abstract: Heme oxygenase consists of two structurally related isozymes, heme oxygenase-1 and and heme oxygenase-2, each of which cleaves heme to form biliverdin, iron and carbon monoxide. Expression of heme oxygenase-1 is increased or decreased depending on cellular microenvironments, whereas little is known about the regulation of heme oxygenase-2 expression. Here we show that hypoxia (1% oxygen) reduces the expression levels of heme oxygenase-2 mRNA and protein after 48 h of incubation in human cell lines, including Jurkat T-lymphocytes, YN-1 and K562 erythroleukemia, HeLa cervical cancer, and HepG2 hepatoma, as judged by northern blot and western blot analyses. In contrast, the expression level of heme oxygenase-1 mRNA varies under hypoxia, depending on the cell line; it was increased in YN-1 cells, decreased in HeLa and HepG2 cells, and remained undetectable in Jurkat and K562 cells. Moreover, heme oxygenase-1 protein was decreased in YN-1 cells under the conditions used, despite the induction of heme oxygenase-1 mRNA under hypoxia. The heme oxygenase activity was significantly decreased in YN-1, K562 and HepG2 cells after 48 h of hypoxia. To explore the mechanism for the hypoxia-mediated reduction of heme oxygenase-2 expression, we showed that hypoxia shortened the half-life of heme oxygenase-2 mRNA (from 12 h to 6 h) in YN-1 cells, without affecting the half-life of heme oxygenase-1 mRNA (9.5 h). Importantly, the heme contents were increased in YN-1, HepG2 and HeLa cells after 48 h of incubation under hypoxia. Thus, the reduced expression of heme oxygenase-2 may represent an important adaptation to hypoxia in certain cell types, which may contribute to the maintenance of the intracellular heme level.
authors.affiliation: Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Furuyama
authors.forename: Kiriko
authors.initials: K
authors.lastname: Kaneko
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Ding
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogawa
authors.forename: Miki
authors.initials: M
authors.lastname: Yoshizawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Kawamura
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takeda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shibahara
mesh_terms: D000064:Acclimatization / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D006207:Half-Life; D006367:HeLa Cells; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D020014:K562 Cells; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D006418:Heme; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2