Haem oxygenase-I: non-canonical roles in physiology and pathology

HO-I (haem oxygenase-I) is a ubiquitously expressed inducible enzyme degrading haem to CO, biliverdin and Fe2+. Its activation reduces oxidative stress in cells and inhibits inflammation, both due to removal of haem and because of the biological activity of HO-I products. CO may act similarly to NO, activating soluble guanylate cyclase and elevating cGMP production. It inhibits platelet aggregation, reduces leucocyte adhesion, decreases apoptosis and lowers the production of some pro-inflammatory cytokines. Biliverdin is converted into bilirubin by biliverdin reductase, and both compounds are potent antioxidants, free radical scavengers and inhibitors of the complement cascade. Iron ions can be potentially toxic, increasing the generation of hydroxyl radicals, but simultaneous induction of ferritin and activation of the Fe-ATPase iron transporter protects cells from oxidative stress. Importantly, basal and induced expression of HO-I is very variable in the human population because of the highly polymorphic (GT)n fragment in the promoter, which may have clinical relevance. The recognized roles of HO-1 are far beyond cytoprotection. The enzyme is important in the regulation of cell proliferation, differentiation and apoptosis. Its activity improves neovascularization, attenuates inflammation and modulates the immune response, thereby influencing carcinogenesis, wound healing, transplant survival and the progression of cardiovascular diseases. Recent results indicate that HO-I may also act through the regulation of microRNAs, which suggests a much broader involvement of HO-1 in the modulation of cell functions and offers a potential explanation for some well-known activities whose mechanism has hitherto been unclear.