Human Hp1-1 and Hp2-2 Phenotype-Specific Haptoglobin Therapeutics Are Both Effective <i>In Vitro</i> and in Guinea Pigs to Attenuate Hemoglobin Toxicity

Lipiski, Miriam; Deuel, Jeremy; Baek, Jin Hyen; Engelsberger, Wolfgang R.; Buehler, Paul W.; Schaer, Dominik J.

doi:10.1089/ars.2012.5089

Cited by 67 publications

(88 citation statements)

References 42 publications

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“…Hb a and b subunits, however, were detected in the cell lysates (41,42). Although it is possible that some Hb is bound to cell membrane, up-regulation of HO-1 is a strong indication of the internalization of the protein in our experiment.…”

Section: Effect Of Oxidized Hb Exposure On E10 Cellsmentioning

confidence: 61%

Oxidized Ferric and Ferryl Forms of Hemoglobin Trigger Mitochondrial Dysfunction and Injury in Alveolar Type I Cells

Chintagari

Jana

Alayash

2016

Am J Respir Cell Mol Biol

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Lung alveoli are lined by alveolar type (AT) 1 cells and cuboidal AT2 cells. The AT1 cells are likely to be exposed to cell-free hemoglobin (Hb) in multiple lung diseases; however, the role of Hb redox (reduction-oxidation) reactions and their precise contributions to AT1 cell injury are not well understood. were reversed by the addition of scavenger proteins, haptoglobin and hemopexin. Collectively, these data establish, for the first time, a central role for cell-free Hb in lung epithelial injury, and that these effects are mediated through the redox transition of Hb to higher oxidation states.

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Section: Effect Of Oxidized Hb Exposure On E10 Cellsmentioning

confidence: 61%

Oxidized Ferric and Ferryl Forms of Hemoglobin Trigger Mitochondrial Dysfunction and Injury in Alveolar Type I Cells

Chintagari

Jana

Alayash

2016

Am J Respir Cell Mol Biol

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“…Studies presented here are restricted to the multimeric Hp phenotype. However, based on earlier studies, in which we confirmed that monomeric and multimeric have identical activity against Hb-triggered hypertension, we do not assume that this polymorphism would significantly affect the compartmentalization function of Hp (24).…”

Section: Discussionmentioning

confidence: 74%

“…The identity, purity, and function of the protein were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), polyacrylamide gel electrophoresis, and surface plasmon resonance as described (24). Hemoglobin was purified from outdated blood, as previously described (24). Hb concentrations were determined by spectrophotometry and are given as molar concentration of total heme (1 M Hb tetramer is therefore equivalent to 4 M heme).…”

Section: Methodsmentioning

confidence: 99%

“…Hp inhibits Hb-triggered protein and lipid oxidation, whereas the large size of the Hb:Hp complex prevents renal Hb excretion and kidney injury (6,21,22). However, the most intriguing and presently unexplained protective function of Hp is its ability to attenuate hypertension that is triggered by cell-free Hb (6,(23)(24)(25). Because the NO reaction rates are comparable for Hb and the Hb:Hp complex (23,26), we hypothesize that the large Hb:Hp complex may shield vascular NO by limiting cell-free Hb decompartmentalization from the vascular lumen to the sites of vascular NO activity.…”

mentioning

confidence: 99%

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Haptoglobin Preserves Vascular Nitric Oxide Signaling during Hemolysis

Schaer¹,

Deuel²,

Schildknecht³

et al. 2016

Am J Respir Crit Care Med

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Rationale: Hemolysis occurs not only in conditions such as sickle cell disease and malaria but also during transfusion of stored blood, extracorporeal circulation, and sepsis. Cell-free Hb depletes nitric oxide (NO) in the vasculature, causing vasoconstriction and eventually cardiovascular complications. We hypothesize that Hb-binding proteins may preserve vascular NO signaling during hemolysis.Objectives: Characterization of an archetypical function by which Hb scavenger proteins could preserve NO signaling during hemolysis.Methods: We investigated NO reaction kinetics, effects on arterial NO signaling, and tissue distribution of cell-free Hb and its scavenger protein complexes.Measurements and Main Results: Extravascular translocation of cell-free Hb into interstitial spaces, including the vascular smooth muscle cell layer of rat and pig coronary arteries, promotes vascular NO resistance. This critical disease process is blocked by haptoglobin. Haptoglobin does not change NO dioxygenation rates of Hb; rather, the large size of the Hb:haptoglobin complex prevents Hb extravasation, which uncouples NO/Hb interaction and vasoconstriction. Size-selective compartmentalization of Hb functions as a substitute for red blood cells after hemolysis and preserves NO signaling in the vasculature. We found that evolutionarily and structurally unrelated Hb-binding proteins, such as PIT54 found in avian species, functionally converged with haptoglobin to protect NO signaling by sequestering cell-free Hb in large protein complexes.Conclusions: Sequential compartmentalization of Hb by erythrocytes and scavenger protein complexes is an archetypical mechanism, which may have supported coevolution of hemolysis and normal vascular function. Therapeutic supplementation of Hb scavengers may restore vascular NO signaling and attenuate disease complications in patients with hemolysis.

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“…Once bound to Hb, several functions of Hp are responsible for its tissue protective effects [5,6]. One of the essential functions of Hp is to attenuate Hb-induced oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Spin trapping combined with quantitative mass spectrometry defines free radical redistribution within the oxidized hemoglobin:haptoglobin complex

Vallelian

García-Rubio

Puglia

et al. 2015

Free Radical Biology and Medicine

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Human Hp1-1 and Hp2-2 Phenotype-Specific Haptoglobin Therapeutics Are Both Effective In Vitro and in Guinea Pigs to Attenuate Hemoglobin Toxicity

Abstract: The present data do not provide support for the concept that phenotype-specific Hp therapeutics offer differential efficacy in mitigating acute Hb toxicity.

Cited by 67 publications

References 42 publications

Oxidized Ferric and Ferryl Forms of Hemoglobin Trigger Mitochondrial Dysfunction and Injury in Alveolar Type I Cells

Oxidized Ferric and Ferryl Forms of Hemoglobin Trigger Mitochondrial Dysfunction and Injury in Alveolar Type I Cells

Haptoglobin Preserves Vascular Nitric Oxide Signaling during Hemolysis

Spin trapping combined with quantitative mass spectrometry defines free radical redistribution within the oxidized hemoglobin:haptoglobin complex

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