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.