| Scientific Background: | Heme oxygenase-2 (HO-2), the constitutive isoform of heme oxygenase, catalyzes the NADPH, O and cytochrome P450 reductase dependent oxidation of heme to carbon monoxide, iron and biliverdin (immediately reduced to bilirubin). These products of the HO reaction render important physiological effects. Carbon monoxide becomes a potent vasodilator, biliverdin and its product bilirubin function as potent antioxidants, and ‘free’ iron increases oxidative stress and regulates the expression of many mRNAs (e.g., DCT-1, ferritin and transferrin receptor) by affecting the conformation of iron regulatory protein-1 (IRP-1) and its binding to iron regulatory elements (IREs) in the 5’- or 3’-UTRs of the mRNAs. To date, researchers have identified heme oxygenase isoforms HO- 1, HO-2 and HO-3. The mRNA and activity of HO-1/Hsp32, a ubiquitous major heat shock/stress response protein, can be increased several-fold by heme, other metalloporphyrins, transition metals and stimuli that induce cellular stress. In contrast to HO-1, HO-2 is highly concentrated in neurons and testes1. Researchers identified multiple HO-2 transcripts which differ in size and use 3 different 5’ untranslated regions (referred to as rHO-2, rHO-2-1 and rHO-2-2) and 2 poly(A) signals, also characterizing a functional glucocorticoid response element (GRE) in the promoter region of rHO-2. In the adult rat testis, data shows developmentally regulated expression of two transcripts for HO-2 of ~2.1kb and ~1.45kb not present in the brain, kidney, thymus, heart, spleen, liver or in prepubertal 14 day old rat testis. Both transcripts exclusively use rHO-2 and contain all coding region exons present in the ~1.3kb and ~1.9kb transcripts and common to all other organs, including the adult and prepubertal rat testis. This data suggests that glucocorticoids control HO-2 levels in the testis, and that developmental and tissue-specific factors determine generation of transcripts unique to the organ. The apparent exclusive use of rHO- 2 by the mature testis indicates HO-2 may play a role in male reproduction. |
