Routes to
            <i>S</i>
            -nitroso-hemoglobin formation with heme redox and preferential reactivity in the β subunits

Luchsinger, Benjamin P.; Rich, Eric N.; Gow, Andrew J.; Williams, Evelyn W.; Stamler, Jonathan S.; Singel, David J.

doi:10.1073/pnas.0233287100

Cited by 202 publications

(218 citation statements)

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“…In one of these proposed mechanisms, MetHb is a reactive intermediate in the production of S-nitrosylated Hb (SNO-Hb); a form of Hb that may subsequently release NO in hypoxic vascular beds. 16,17 Experimental data in support of another proposed mechanism suggest that the stable NO metabolite nitrite (NO 2 -) may provide a physiological source of bioactive NO by deoxygenated hemoglobin (deoxyHb), which can act as a nitrite reductase under allosteric and pH control via the following reaction: Nitrite [NO 2 -] ? deoxyHb ?…”

Section: Résumémentioning

confidence: 99%

Plasma methemoglobin as a potential biomarker of anemic stress in humans

Hare

Romaschin

et al. 2012

Can J Anesth/J Can Anesth

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Purpose Transfusion of allogeneic red blood cells (RBCs) is one of the main treatments of acute anemia secondary to blood loss and fluid resuscitation within the operating room. Decisions to transfuse blood are based largely on intermediate biological markers (hemoglobin, arterial oxygen saturation, blood pressure, heart rate) which may not accurately reflect inadequacy of tissue oxygen delivery.Based on experimental studies, we hypothesized that anemia-induced tissue hypoxia activates adaptive mechanisms which promote local vascular nitric oxide (NO) production to improve tissue perfusion and survival during acute anemia. Hemoglobin (Hb) oxidation to methemoglobin (MetHb) may be a byproduct of such local NO production. Therefore, we tested the hypothesis that MetHb is a biomarker of hypoxic-anemic stress during acute hemodilution associated with cardiopulmonary bypass. Methods With institutional ethics approval, routine laboratory arterial blood gas and co-oximetry values were obtained from 295 patients undergoing heart surgery during February 1 to September 30, 2010, and the values were assessed retrospectively. All samples with an arterial oxygen saturation value C90% were included (n = 1,421). The maximal change in Hb associated with hemodilution on cardiopulmonary bypass was determined within 48 hr of surgery (n = 180). A chart review was performed to determine the incidence of RBC transfusion and exogenous nitrate administration. All anonymous data were analyzed by linear regression to determine the relationship between Author contributions Gregory M.T. Hare designed the research, performed the research, contributed novel intellectual input, analyzed the data, and wrote the paper. Alexander Mu performed the research, contributed novel intellectual input, and analyzed the data. Alexander Romaschin designed the research, performed the research, contributed novel intellectual input, and analyzed the data. Nadine Shehata designed the research, performed the research, contributed novel intellectual input, and analyzed the data. W. Scott Beattie designed the research, performed the research, contributed novel intellectual input, analyzed the data, and wrote the paper. C. David Mazer designed the research, performed the research, contributed novel intellectual input, analyzed the data, and wrote the paper. Albert K.Y. Tsui contributed novel intellectual input, analyzed the data, and wrote the paper. RésuméObjectif La transfusion de globules rouges alloge´niques est l'un des principaux traitements de l'ane´mie aigues econdaire a`une perte sanguine et au remplissage liquidien en salle d'ope´ration. La de´cision de transfuser du sang repose essentiellement sur des marqueurs biologiques interme´diaires (he´moglobine, saturation en oxyge`ne du sang arte´riel, pression arte´rielle, fre´quence cardiaque) qui pourraient ne pas refle´ter avec pre´cision l'insuffisance d'apport d'oxyge`ne aux tissus. A`partir d'e´tudes expe´rimentales nous avons fait l'hypothe`se qu'une hypoxie tissulaire induite par l'ane´mie act...

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Section: Résumémentioning

confidence: 99%

Plasma methemoglobin as a potential biomarker of anemic stress in humans

Hare

Romaschin

et al. 2012

Can J Anesth/J Can Anesth

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“…These results call into question mechanisms, which require increased O 2 affinity as a consequence of HbNO formation. Other investigators have determined that limited exposure of deoxy Hb to NO leads to nitrosylation of β-subunit hemes and subsequent oxygenation leads to the formation of SNO-Hb [12]. Formation of SNO-Hb primarily occurs when NO binds to the β93 Cys residues [13][14][15] and the S-nitroso form of hemoglobin has been observed to exhibit increased O 2 affinity [16].…”

Section: Introductionmentioning

confidence: 99%

The role of β93 Cys in the inhibition of Hb S fiber formation

Knee

Roden

Flory

et al. 2007

Biophysical Chemistry

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Recent studies have suggested that nitric oxide (NO) binding to hemoglobin (Hb) may lead to the inhibition of sickle cell fiber formation and the dissolution of sickle cell fibers. NO can react with Hb in at least 3 ways: 1) formation of Hb(II)NO, 2) formation of methemoglobin, and 3) formation of S-nitrosohemoglobin, through nitrosylation of the β93 Cys residue. In this study, the role of β93 Cys in the mechanism of sickle cell fiber inhibition is investigated through chemical modification with N-ethylmaleimide. UV resonance Raman, FT-IR and electrospray ionization mass spectroscopic methods in conjunction with equilibrium solubility and kinetic studies are used to characterize the effect of β93 Cys modification on Hb S fiber formation. Both FT-IR spectroscopy and electrospray mass spectrometry results demonstrate that modification can occur at both the β93 and α104 Cys residues under relatively mild reaction conditions. Equilibrium solubility measurements reveal that singlymodified Hb at the β93 position leads to increased amounts of fiber formation relative to unmodified or doubly-modified Hb S. Kinetic studies confirm that modification of only the β93 residue leads to a faster onset of polymerization. UV resonance Raman results indicate that modification of the α104 residue in addition to the β93 residue significantly perturbs the α 1 β 2 interface, while modification of only β93 does not. These results in conjunction with the equilibrium solubility and kinetic measurements are suggestive that modification of the α104 Cys residue and not the β93 Cys residue leads to T-state destabilization and inhibition of fiber formation. These findings have implications for understanding the mechanism of NO binding to Hb and NO inhibition of Hb S fiber formation.

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“…NO bound as a ferrous nitrosyl adduct [Fe(II)NO] does not exert direct vasodilatory activity (9)(10)(11)(12), because ligand off rates are slow and any NO liberated is rapidly trapped by the surrounding hemes, which are present at relatively high concentrations (excess heme over NO: Ϸ10,000:1) (12). However, work from our laboratories has elucidated conditions under which ␤-chain heme Fe(II)NO complexes can be oxidatively converted to an S-nitrosothiol (Cys␤SNO), which maintains NO bioactivity (13)(14)(15)(16).…”

mentioning

confidence: 99%

“…Recent work by us (16) and others (21)(22)(23) has shown that oxidized hemes [Fe(III)], particularly ␤-chain hemes, are competent for this redox activity. Thus, ␤Fe(III)NO meets both the oxidative and structural requirements for SNO-Hb production (7,16,23). In related studies, Pezacki et al (18,24) reported that ␤Fe(III)NO accumulates during deoxygenation of SNO-Hb.…”

mentioning

confidence: 99%

“…Thus, ␤Fe(III)NO meets both the oxidative and structural requirements for SNO-Hb production (7,16,23). In related studies, Pezacki et al (18,24) reported that ␤Fe(III)NO accumulates during deoxygenation of 24) To explore the role of Fe(III)NO in SNO-Hb production, we have extended our previous work on reactions of nitrite with deoxyHb (3,7,12,16). Those studies showed that exposure of deoxyHb to limiting nitrite leads to production of Fe(III) and ␤ Fe(II)NO, as described, in simplified terms, in Eq.…”

mentioning

confidence: 99%

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An S -nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate

Angelo

Singel

Stamler³

2006

Proc. Natl. Acad. Sci. U.S.A.

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215

218

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Red blood cells (RBCs) act as O2-responsive transducers of vasodilator and vasoconstrictor activity in lungs and tissues by regulating the availability of nitric oxide (NO). Vasodilation by RBCs is impaired in diseases characterized by hypoxemia. We have proposed that the extent to which RBCs constrict vs. dilate vessels is, at least partly, controlled by a partitioning between NO bound to heme iron and to Cys␤93 thiol of hemoglobin (Hb). Hemes sequester NO, whereas thiols deploy NO bioactivity. In recent work, we have suggested that specific micropopulations of NO-liganded Hb could support the chemistry of S-nitrosohemoglobin (SNO-Hb) formation. Here, by using nitrite as the source of NO, we demonstrate that a (T state) micropopulation of a heme-NO species, with spectral and chemical properties of Fe(III)NO, acts as a precursor to SNO-Hb formation, accompanying the allosteric transition of Hb to the R state. We also show that at physiological concentrations of nitrite and deoxyHb, a S-nitrosothiol precursor is formed within seconds and produces SNO-Hb in high yield upon its prompt exposure to O 2 or CO. Deoxygenation͞reoxygenation cycling of oxyHb in the presence of physiological amounts of nitrite also efficiently produces SNO-Hb. In contrast, high amounts of nitrite or delays in reoxygenation inhibit the production of SNO-Hb. Collectively, our data provide evidence for a physiological S-nitrosothiol synthase activity of tetrameric Hb that depends on NO-Hb micropopulations and suggest that dysfunction of this activity may contribute to the pathophysiology of cardiopulmonary and blood disorders.hypoxic vasodilation ͉ nitric oxide ͉ S-nitrosohemoglobin ͉ S-nitrosylation H istorically, red blood cells (RBCs) have been regarded as transporters of oxygen (O 2 ) and carbon dioxide (CO 2 ), with the uptake of one and release of the other being reciprocally related. With the advent of the field of nitric oxide (NO) biology, RBCs also were thought to be scavengers of NO that could effectively quench its bioactivity. Some years ago, we noted that this limited view was inconsistent with the role of hemoglobin (Hb) in O 2 delivery, as sequestration of NO by Hb would lead to constriction of blood vessels, and this vasoconstriction, in turn, would limit the supply of O 2 (1). We subsequently demonstrated that vasoconstriction by RBCs is seen only at relatively high partial pressures of O 2 (pO 2 ); at lower pO 2 s characteristic of tissues (5-20 mm Hg), RBCs dilate blood vessels (2, 3). Vasodilation (of aortic or pulmonary artery rings) by RBCs in bioassay is rapid, in keeping with the temporal requirements of arterial-venous transit (in seconds) (3, 4). Moreover, when infused into animals, RBCs increase blood flow and improve oxygenation, an indication that RBCs elicit vasodilation in both the systemic and pulmonary circulations (1, 4-6). Collectively, the observation of vasoconstriction by RBCs at higher pO 2 but graded vasodilation with increasing hypoxia appears to provide a mechanism for matching blood flow to metaboli...

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Routes to S -nitroso-hemoglobin formation with heme redox and preferential reactivity in the β subunits

Cited by 202 publications

References 50 publications

Plasma methemoglobin as a potential biomarker of anemic stress in humans

Plasma methemoglobin as a potential biomarker of anemic stress in humans

The role of β93 Cys in the inhibition of Hb S fiber formation

An S -nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate

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