The interaction of nitric oxide with distinct hemoglobins differentially amplifies endothelial heme uptake and heme oxygenase-1 expression.
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.
Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Watford Road, Harrow, Middlesex, HA1 3UJ, UK. r.foresti@imperial.ac.uk
Roberta
R
Foresti
Sandip
S
Bains
Filip
F
Sulc
Patrick J
PJ
Farmer
Colin J
CJ
Green
Roberto
R
Motterlini
D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D002417:Cattle; D018929:Cell Culture Techniques; D002460:Cell Line; D003470:Culture Media; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006427:Hemin / Q000378:metabolism; D006441:Hemoglobin A / Q000378:metabolism; D006451:Hemoglobin, Sickle / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D008706:Methemoglobin / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D013552:Swine; D015854:Up-Regulation
D003470:Culture Media; D006451:Hemoglobin, Sickle; D006454:Hemoglobins; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D006418:Heme; C028881:hemoglobin A(0); D006427:Hemin; D008706:Methemoglobin; D006441:Hemoglobin A; D051547:Heme Oxygenase-1; D001663:Bilirubin