Nitrite reductase activity of hemoglobin as a systemic nitric oxide generator mechanism to detoxify plasma hemoglobin produced during hemolysis

Minneci, Peter C.; Deans, Katherine J.; Shiva, Sruti; Huang, Zhi; Banks, Steven M.; Kern, Steven J.; Natanson, Charles; Solomon, Steven B.; Gladwin, Mark T.

doi:10.1152/ajpheart.00151.2008

Cited by 53 publications

(43 citation statements)

References 87 publications

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“…We also find a correlation between nitrite reductase activity and the protein's oxygen binding properties (P 50 and n 50 ) and this may play a significant role in making these materials non-vasoactive (60). The circulatory site at which the protein's nitrite reductase activity is maximal correlates with the deoxygenation of the protein (P 50 ) (64,90). BT-Hb and BT-PEG are expected to produce NO at physiologically relevant sites with low pO 2 .…”

Section: Discussionmentioning

confidence: 99%

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Enhancing Nitrite Reductase Activity of Modified Hemoglobin: Bis-tetramers and Their PEGylated Derivatives

Lui

Kluger

2009

Biochemistry

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The clinical evaluation of stabilized tetrameric hemoglobin as alternatives to red cells revealed that the materials caused significant increases in blood pressure and related problems and this was attributed to the scavenging of nitric oxide and extravasation. The search for materials with reduced vasoactivity led to the report that conjugates of hemoglobin tetramers and polyethylene glycol (PEG) chains did not elicit these pressor effects. However, this material does not deliver oxygen efficiently due to its lack of cooperativity and high oxygen affinity, making it unsuitable as an oxygen carrier. It has been recently reported that PEGconjugated hemoglobin converts nitrite to nitric oxide at a faster rate than does the native protein, which may compensate for the scavenging of nitric oxide. It is therefore important to alter hemoglobin in order to enhance nitrite reductase activity while retaining its ability to deliver oxygen. If the beneficial effect of PEG is associated with the increased size reducing extravasation, this can also be achieved by coupling cross-linked tetramers to one another, giving materials with appropriate oxygen affinity and cooperativity for use as circulating oxygen carriers. In the present study it is shown that cross-linked bis-tetramers with good oxygen delivery potential have enhanced nitrite reductase activity with k obs = 0.70 M -1 s -1 (24 °C), compared to native protein and cross-linked tetramers, k obs = 0.25 M -1 s -1 and k obs = 0.52 M -1 s -1 , respectively, but are less active in reduction of nitrite than Hb-PEG5K 2 (k obs = 2.5 M -1 s -1 ). However, conjugation of four PEG chains to the bis-tetramer (at each β-Cys-93) produces a material with greatly increased nitrite reductase activity (k obs = 1.8 M -1 s -1 ) while retaining cooperativity (P 50 = 4.1, n 50 = 2.4). Thus, PEGylated bistetramers combine increased size and enhanced nitrite reductase activity expected for decreased vasoactivity with characteristics of an acceptable HBOC.

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Section: Discussionmentioning

confidence: 99%

“…The site at which the rate of NO production is fastest depends directly on the HBOC's P 50 (64,90). BT-Hb and BT-PEG both have high oxygen affinities (P 50 = 9.3 and 4.1 respectively).…”

Section: Nitrite Reductase Activity At Physiologically Relevant Sitesmentioning

confidence: 99%

Enhancing Nitrite Reductase Activity of Modified Hemoglobin: Bis-tetramers and Their PEGylated Derivatives

Lui

Kluger

2009

Biochemistry

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“…10,14 Systemic infusions of nitrite in dogs exhibit both arteriolar and venous dilation, with more potent effects on the systemic vascular resistance, increasing cardiac output. 15 Numerous normal human volunteer studies have now demonstrated that nitrate supplementation can increase exercise efficiency, as defined by total oxygen consumption (V ⋅ o 2 ) for total work performed (Watts). 11 In preclinical studies, nitrite has been shown to exhibit therapeutic efficacy in mouse, rat, and sheep models of pulmonary hypertension and mouse models of heart failure.…”

Section: Articles See P 371 and P 381mentioning

confidence: 99%

Harnessing the Nitrate–Nitrite–Nitric Oxide Pathway for Therapy of Heart Failure With Preserved Ejection Fraction

Vanderpool

Gladwin

2015

Circulation

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“…Although only deoxy heme catalyzes the reaction, O 2 tensions that half-saturate Hb maximize the release of NO-equivalents to the vasculature, as evidenced by nitrite-induced vasorelaxation (49,53,75). This has been attributed to the redox potential shift associated with formation of some R-state Hb as O 2 is bound (49,53,75). However, it is more appropriately ascribed to a shift in kinetics of the reaction than to the redox potential, which specifies the thermodynamic driving potential for heme oxidation/reduction and does not define the reaction rate (see Thermodynamic and kinetic aspects of Hb oxidation section).…”

Section: Redox Reactions Of Hb With Nitritementioning

confidence: 99%

“…Specifically, NO-dependent reactions involving formation of SNO-Hb have been shown to be under the control of allosteric reactions that alter the reactivity of b93Cys (8,65). In addition, in the presence of nitrite, Hb functions as an allosteric nitrite reductase, with maximal NO generation around the intrinsic oxygen affinity (P 50 ) of Hb, suggestive of allosteric controls of this reaction (75). It is by virtue of the differences in reactivity of Hb's R-and T-states that its reactions with nitrites and/or formation of SNO-Hb have been proposed to have specific therapeutic application during intravascular hemolysis and during administration of Hb-based blood substitutes, or even as means of reversing of storage-induced alterations in the properties of red blood cells (75).…”

Section: Redox Properties Of Structurally Diverse Hbsmentioning

confidence: 99%

Molecular Controls of the Oxygenation and Redox Reactions of Hemoglobin

Bonaventura

Henkens

Alayash

et al. 2013

Antioxidants & Redox Signaling

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Significance: The broad classes of O 2 -binding proteins known as hemoglobins (Hbs) carry out oxygenation and redox functions that allow organisms with significantly different physiological demands to exist in a wide range of environments. This is aided by allosteric controls that modulate the protein's redox reactions as well as its O 2 -binding functions. Recent Advances: The controls of Hb's redox reactions can differ appreciably from the molecular controls for Hb oxygenation and come into play in elegant mechanisms for dealing with nitrosative stress, in the malarial resistance conferred by sickle cell Hb, and in the as-yet unsuccessful designs for safe and effective blood substitutes. Critical Issues: An important basic principle in consideration of Hb's redox reactions is the distinction between kinetic and thermodynamic reaction control. Clarification of these modes of control is critical to gaining an increased understanding of Hb-mediated oxidative processes and oxidative toxicity in vivo. Future Directions: This review addresses emerging concepts and some unresolved questions regarding the interplay between the oxygenation and oxidation reactions of structurally diverse Hbs, both within red blood cells and under acellular conditions. Developing methods that control Hbmediated oxidative toxicity will be critical to the future development of Hb-based blood substitutes. Antioxid. Redox Signal. 18, 2298-2313. General PrinciplesEmergence of proteins capable of transporting O 2 I n this review, we examine the adaptive changes in the molecular controls of hemoglobin (Hb) oxygenation and oxidation that have evolved to meet the highly varied physiological and environmental demands of respiring organisms. Globins came into being during the planet's long early period of anoxia/hypoxia, and recent studies show that globins are either expressed or inducible in almost all cells (98). Studies have shown that one evolutionary pathway of Hb is that of a multipurpose domain attached to a variety of unrelated proteins, thus forming molecules with different functions (126). This pathway has allowed structurally distinct Hbs to evolve: (i) to protect against the high levels of nitrosative stress of the earth's early environment; (ii) to protect against O 2 -linked oxidation; (iii) to act as O 2 sensors that help regulate the expression of proteins during periods of hypoxia or anoxia; and (iv) to enable aerobic respiration by facilitating diffusion and/or acting as O 2 carriers (44,56,57,70,71,73,107). A common theme in the fascinating story of Hb evolution is the emergence of distinct mechanisms for controlling Hb's oxygenation and redox functions.Since increased amounts of O 2 were released in our planet's early history, O 2 toxicity brought about species extinction on a global scale. On the other hand, this ''oxygen pollution'' made possible a new biological process, that of aerobic respiration. A tremendous gain in the energy obtainable from oxidation of energy-rich metabolites was achieved when organisms evolve...

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Nitrite reductase activity of hemoglobin as a systemic nitric oxide generator mechanism to detoxify plasma hemoglobin produced during hemolysis

Cited by 53 publications

References 87 publications

Enhancing Nitrite Reductase Activity of Modified Hemoglobin: Bis-tetramers and Their PEGylated Derivatives

Enhancing Nitrite Reductase Activity of Modified Hemoglobin: Bis-tetramers and Their PEGylated Derivatives

Harnessing the Nitrate–Nitrite–Nitric Oxide Pathway for Therapy of Heart Failure With Preserved Ejection Fraction

Molecular Controls of the Oxygenation and Redox Reactions of Hemoglobin

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