Hypoxia and Heme Oxygenases: Oxygen Sensing and Regulation of Expression

Heme is an essential molecule for life, as it is involved in sensing and using oxygen. Heme must be synthesized and degraded within an individual nucleated cell. Physiologic heme degradation is catalyzed by two functional isozymes of heme oxygenase, heme oxygenase-1 (HO-1) and HO-2, yielding carbon monoxide, iron, and biliverdin, an immediate precursor to bilirubin. HO-1 is an inducible enzyme, but the expression level of HO-2 is maintained in a narrow range. Characteristically, human HO-1 contains no Cys residue, whereas human HO-2 contains three Cys residues, each of which might be involved in heme binding. These features suggest separate physiologic roles of HO-1 and HO-2. Recent studies have shown that the expression levels of HO-1 and HO-2 are reduced under hypoxia, depending on the cell types. Moreover, we have proposed HO-2 as a potential O₂ sensor, because HO-2–deficient mice show hypoxemia and a blunted hypoxic ventilatory response with normal hypercapnic ventilatory response. HO-2–deficient mice also show hypertrophy of the pulmonary venous myocardium and enlargement of the carotid body. These morphometric changes are attributable to chronic hypoxemia. Here, we update the understanding of the regulation of HO-1 and HO-2 expression and summarize the regulatory role of HO-2 in the intercellular communication.