Hemoglobin α in Pulmonary Endothelium: Ironing Out Nitric Oxide Signaling

In the presence of oxygen, ferrous oxyhemoglobin a (Fe12) scavenges NO by the dioxygenase reaction, with NO reacting with O2-bound Hb a (Fe12- O2) to form nitrate (NO32) and ferric (Fe13) Hb a as products (5). [...]the redox state of the heme controls NO diffusion: when it is reduced and oxygenated, Hb a inhibits NO signaling, and when it is oxidized in the ferric form, Hb a allows NO to diffuse from endothelium to smooth muscle (Figure 1). A number of studies have suggested that they catalyze electron transfer reactions, such as the reaction with nitrite (NO2~) to form NO under hypoxic conditions, NO scavenging reactions under oxygenated conditions, reactive oxygen and nitrogen species detoxification, and peroxidase reactions that generate oxidized free fatty acids, and are involved in signaling events that appear to protect against apoptosis (8-10). Because these reactions occur at fast rates (rate constant ~6-8 X 107 M2 s2 for Hb a) and at low globin concentrations, they can effectively scavenge NO, decreasing NO diffusional gradients, and thus may provide a mechanism to finely regulate NO signaling (14). From a therapeutic perspective, treatment with Hb a peptide is able to increase intracellular phospho vasodilator-stimulated phosphoprotein, a specific marker of cyclic guanosine monophosphate/protein kinase G-dependent signaling, suggesting that targeting Hb a within pulmonary ECs in patients with PAH will relieve endothelial dysfunction through activation of the sGC pathway.