Assessments of the chemistry and vasodilatory activity of nitrite with hemoglobin under physiologically relevant conditions

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

doi:10.1016/j.jinorgbio.2004.12.010

Cited by 79 publications

(89 citation statements)

References 47 publications

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“…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.…”

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confidence: 90%

“…The chemistry of vasoconstriction involves, among other reactions, NO binding to the ferrous hemes of Hb (1,(7)(8)(9). 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).…”

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confidence: 99%

“…with SNO-Hb produced upon prompt oxygenation (12,(15)(16)(17). However, our kinetic analysis (12), like other work on nitrite͞Hb interactions (25)(26)(27), was performed at supraphysiological nitrite͞Hb ratios (typically nitrite:Hb 1:10-10:1 vs. Ϸ1:1,000 in vivo), with a global spectral deconvolution approach that was not adapted to recognize ''minority species.''…”

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confidence: 99%

“…However, our kinetic analysis (12), like other work on nitrite͞Hb interactions (25)(26)(27), was performed at supraphysiological nitrite͞Hb ratios (typically nitrite:Hb 1:10-10:1 vs. Ϸ1:1,000 in vivo), with a global spectral deconvolution approach that was not adapted to recognize ''minority species.'' We now examine the product distribution of reactions of nitrite and deoxyhemoglobin by using a modified approach in which spectral deconvolution is used to test for the presence of minority species formed at physiologically relevant concentrations, whereas studies of the chemical reactivity of these species are used to verify their identity.…”

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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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confidence: 90%

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confidence: 99%

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confidence: 99%

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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.

Self Cite

215

218

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“…Exposure to nitrite also leads to the formation of measurable amounts of SNO-Hb and an arterial to venous gradient of nitrite [24]. The organ chamber bioassay experiments of Stamler and co-workers, however, are suggestive that the reaction of nitrite and deoxy Hb does not relax blood vessels unless SNO-Hb is formed [26] and that SNO-Hb formation involves a Fe(III)NO precursor [27]. One significant difference between the two models lies in the role of SNO-Hb as an intermediate in the process of NO delivery.…”

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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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The Main Players: Hemoglobin and Myoglobin; Nitric Oxide and Oxygen

McMahon

Bonaventura

2011

Chemistry and Biochemistry of Oxygen Therapeutics

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Assessments of the chemistry and vasodilatory activity of nitrite with hemoglobin under physiologically relevant conditions

Cited by 79 publications

References 47 publications

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

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

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

The Main Players: Hemoglobin and Myoglobin; Nitric Oxide and Oxygen

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