Hypoxia reduces the expression of heme oxygenase‐2 in various types of human cell lines

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.