Physiologic roles for the heme oxygenase products carbon monoxide, bilirubin and iron: Links to neuroprotection in stroke and Alzheimer's disease

Heme oxygenase (HO) cleaves the heme ring releasing iron, carbon monoxide (CO) and biliverdin, which is immediately reduced to bilirubin by the abundant biliverdin reductase. Recent research indicates major cellular roles for all three HO products. The constitutive isoform, heme oxygenase 2 (HO2), is concentrated in the brain with discrete localizations resembling soluble guanylyl cyclase, implying a role in regulating cyclic guanosine monophosphate (cGMP). HO2 is localized to myenteric plexus neurons of the intestine similar to neuronal nitric oxide synthase (nNOS). Mice with targeted deletion of HO2 or nNOS each display marked reductions in non-adrenergic-non-cholinergic neurotransmission and cGMP levels indicating a neurotransmitter role for the two gases acting as co-transmitters. HO2 is localized to the endothelial cell layer of blood vessels as well as neurons in the adventitial layer. HO inhibitors reduce nitric oxide (NO)-independent vasodilation implicating CO as an endothelial derived relaxing factor. Bilirubin, formed from HO2, appears to be a physiologic neuroprotectant. Neurotoxicity is augmented in brain cultures from HO2 gene knockout mice which also display augmented neural damage following cerebral vascular occlusion. Very low concentrations of bilirubin reverse the neurotoxicity. Heme oxygenase 1 (HO1) plays a role in iron efflux from cells. Iron efflux is diminished in cells from HO1 gene knockout mice, while HO1 transfection augments efflux. Iron dependent cytotoxicity is worsened in HO1 gene knockout cells while HO1 transfection alleviates the toxicity.