Heme oxygenase: Recent advances in understanding its regulation and role

Heme oxygenase (HO) is responsible for the physiological breakdown of heme into equimolar amounts of biliverdin, carbon monoxide, and iron. Three isof orms (HO-1, HO-2, and HO-3) have been identified. HO-1 is ubiquitous and it s mRNA and activity can be increased several-fold by heme, other metallopor phyrins, transition metals, and stimuli that induce cellular stress. HO-1 i s recognized as a major heat shock/stress response protein. Recent work fro m our laboratory has demonstrated several potential consensus regulatory el ements in the 5'-untranslated region (UTR) of HO-1, including activator pro tein 1 (AP-1), metal responsive element (MRE), oncogene c-myc/max heterodim er binding site (Myc/Max), antioxidant response element (ARE), and GC box b inding (Sp 1) sites. Using deletion-reporter gene constructs, we have mappe d sites that mediate the arsenite-dependent induction of HO-1, and we have shown that components of the extracellular signal-regulated kinase (ERK) an d p38 (a homologue of the yeast HOG1 kinase), but not c-jun N-terminal kina se (JNK), mitogen-activated protein (MAP) kinase pathways are involved in a rsenite-dependent upregulation. In contrast, HO-2 is present chiefly in the brain and testes and is virtually uninducible. HO-3 has very low activity; its physiological function probably involves heme binding. Products of the HO reaction have important effects: carbon monoxide is a potent vasodilato r, which is thought to play a key role in the modulation of vascular tone, especially in the liver under physiological conditions, and in many organs under "stressful" conditions associated with HO-1 induction. Biliverdin and its product bilirubin, formed in most mammals, are potent antioxidants. In contrast,"free" iron increases oxidative stress and regulates the expressi on of many mRNAs (e.g., DCT-1, ferritin, and transferrin receptor) by affec ting the conformation of iron regulatory protein (IRP)-1 and its binding to iron regulatory elements (IREs) in the 5'- or 3'-UTRs of the mRNAs.