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CARDIOVASCULAR

The Interaction of Nitric Oxide with Distinct Hemoglobins Differentially Amplifies Endothelial Heme Uptake and Heme Oxygenase-1 Expression

Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, United Kingdom (R.F., S.B., C.J.G., R.M.); and Department of Chemistry, University of California, Irvine, Irvine, California (F.S., P.J.F.)

Heme is a strong inducer and substrate of the stress protein heme oxygenase-1 (HO-1), which produces carbon monoxide, iron, and bilirubin. We have reported recently that nitric oxide (NO) augments the incorporation of free hemin in endothelial cells, resulting in amplified HO-1 expression and production of bilirubin. Here, we extend our studies by showing that both NO⁺ and NO^– donors interacted with reduced (HbA₀) or oxidized (metHb) hemoglobin, as well as hemoglobin from sickle cell disease (HbS), to strongly magnify HO-1, with a pattern of induction dependent on the oxidation state of the hemoglobin used. A corresponding enhancement of endothelial heme uptake was observed following exposure of HbA₀ or HbS to the NO donors, which also increased the uptake of free hemin. We postulated that this effect may be caused by formation of heme-nitrosyl (H-NO) complexes, and indeed endothelial cells exposed to preformed H-NO showed greater heme incorporation than free hemin. Furthermore, NO donors directly affected the permeability of membranes to free hemin. In conclusion, our data indicate a novel role for NO in the modulation of heme transport and HO-1 induction in endothelial cells, which may be relevant for hematological disorders characterized by disruption of the heme-NO equilibrium.

Address correspondence to: Dr. Roberta Foresti, Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Watford Road, Harrow, Middlesex, HA1 3UJ, UK. E-mail: r.foresti{at}imperial.ac.uk