βCysteine 93 in human hemoglobin: a gateway to oxidative stability in health and disease

Alayash, Abdu I.

doi:10.1038/s41374-020-00492-3

Cited by 18 publications

(13 citation statements)

References 56 publications

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“…Multiple evidence indicates that βCys93 is an important hotspot of free radical-induced oxidation in Hb ( 3 , 30 , 54 ). To study the oxidative modification of cysteines, we examined Hb derived from complicated lesions of carotid arteries with mass spectrometry.…”

Section: Resultsmentioning

confidence: 99%

Oxidation of Hemoglobin Drives a Proatherogenic Polarization of Macrophages in Human Atherosclerosis

Balla

Potor

Hendrik

et al. 2021

Antioxidants & Redox Signaling

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The aim of our study was to explore the pathophysiologic role of oxidation of hemoglobin (Hb) to ferrylHb in human atherosclerosis. Results:We observed a severe oxidation of Hb to ferrylHb in complicated atherosclerotic lesions of carotid arteries with oxidative changes of the globin moieties, detected previously described oxidation hotspots in Hb (β1Cys93; β1Cys112; β2Cys112) and identified a novel oxidation hotspot (α1Cys104). After producing a monoclonal anti-ferrylHb antibody, ferrylHb was revealed to be localized extracellularly and also internalized by macrophages in the human hemorrhagic complicated lesions. We demonstrated that ferrylHb is taken up via phagocytosis as well as CD163 receptormediated endocytosis then transported to lysosomes involving actin polymerization.Internalization of ferrylHb was accompanied by up-regulation of heme oxygenase-1 and Hferritin and accumulation of iron within lysosomes as a result of heme/iron uptake.Importantly, macrophages exposed to ferrylHb in atherosclerotic plaques exhibited proinflammatory phenotype, as reflected by elevated levels of IL-1β and TNFα. To find further signatures of ferrylHb in complicated lesions we performed RNA-seq analysis on biopsies from patients who underwent endarterectomies. RNA-seq analysis demonstrated that human complicated lesions had a unique transcriptomic profile which was different from arteries and atheromatous plaques. Pathways affected in complicated lesions included gene changes associated with PI3k signaling, lipid transport, tissue remodeling and vascularization. Targeted analysis of gene expression associated with calcification, apoptosis and hemolytic-specific clusters indicated an increase in the severity of complicated lesions compared to atheroma. A 39% overlap in the differential gene expression profiles of human macrophages exposed to ferrylHb and the complicated lesion profiles was uncovered. Among these 547 genes, we found inflammatory, angiogenesis, and iron metabolism gene clusters regulated in macrophages. Innovation and Conclusion:We conclude that oxidation of Hb to ferrylHb contributes the progression of atherosclerosis via polarizing macrophages into a pro-atherogenic phenotype.

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Section: Resultsmentioning

confidence: 99%

Oxidation of Hemoglobin Drives a Proatherogenic Polarization of Macrophages in Human Atherosclerosis

Balla

Potor

Hendrik

et al. 2021

Antioxidants & Redox Signaling

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“…According to the literature data, the second cysteine of the Hb β-subunit (Cys112β) is located quite far from Cys93β [52], and can hardly be the second amino acid ligand for Hb-DNICs. Such ligands could potentially be His92β, His97β or Asp94β residues located near Cys93β [53].…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Dinitrosyl Iron Complexes Bound with Hemoglobin on Oxidative Modification by Peroxynitrite

Kosmachevskaya

Nasybullina

Шумаев

et al. 2021

IJMS

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Dinitrosyl iron complexes (DNICs) are a physiological form of nitric oxide (•NO) in an organism. They are able not only to deposit and transport •NO, but are also to act as antioxidant and antiradical agents. However, the mechanics of hemoglobin-bound DNICs (Hb-DNICs) protecting Hb against peroxynitrite-caused, mediated oxidative modification have not yet been scrutinized. Through EPR spectroscopy we show that Hb-DNICs are destroyed under the peroxynitrite action in a dose-dependent manner. At the same time, DNICs inhibit the oxidation of tryptophan and tyrosine residues and formation of carbonyl derivatives. They also prevent the formation of covalent crosslinks between Hb subunits and degradation of a heme group. These effects can arise from the oxoferryl heme form being reduced, and they can be connected with the ability of DNICs to directly intercept peroxynitrite and free radicals, which emerge due to its homolysis. These data show that DNICs may ensure protection from myocardial ischemia.

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“…Hb oxidation is implicated in the pathogenesis of atherosclerotic plaque progression [18], as well as in other hemolytic diseases [11][12][13]44]. Having shown that A1M is induced by the Hb oxidation products heme and FerrylHb, we next examined whether A1M inhibits the process of Hb oxidation.…”

Section: Ra1m Inhibits Hb Oxidationmentioning

confidence: 99%

Ferryl Hemoglobin and Heme Induce A1-Microglobulin in Hemorrhaged Atherosclerotic Lesions with Inhibitory Function against Hemoglobin and Lipid Oxidation

Pethő

Gáll

Hendrik

et al. 2021

IJMS

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Infiltration of red blood cells into atheromatous plaques and oxidation of hemoglobin (Hb) and lipoproteins are implicated in the pathogenesis of atherosclerosis. α1-microglobulin (A1M) is a radical-scavenging and heme-binding protein. In this work, we examined the origin and role of A1M in human atherosclerotic lesions. Using immunohistochemistry, we observed a significant A1M immunoreactivity in atheromas and hemorrhaged plaques of carotid arteries in smooth muscle cells (SMCs) and macrophages. The most prominent expression was detected in macrophages of organized hemorrhage. To reveal a possible inducer of A1M expression in ruptured lesions, we exposed aortic endothelial cells (ECs), SMCs and macrophages to heme, Oxy- and FerrylHb. Both heme and FerrylHb, but not OxyHb, upregulated A1M mRNA expression in all cell types. Importantly, only FerrylHb induced A1M protein secretion in aortic ECs, SMCs and macrophages. To assess the possible function of A1M in ruptured lesions, we analyzed Hb oxidation and heme-catalyzed lipid peroxidation in the presence of A1M. We showed that recombinant A1M markedly inhibited Hb oxidation and heme-driven oxidative modification of low-density lipoproteins as well plaque lipids derived from atheromas. These results demonstrate the presence of A1M in atherosclerotic plaques and suggest its induction by heme and FerrylHb in the resident cells.

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βCysteine 93 in human hemoglobin: a gateway to oxidative stability in health and disease

Cited by 18 publications

References 56 publications

Oxidation of Hemoglobin Drives a Proatherogenic Polarization of Macrophages in Human Atherosclerosis

Oxidation of Hemoglobin Drives a Proatherogenic Polarization of Macrophages in Human Atherosclerosis

Protective Effect of Dinitrosyl Iron Complexes Bound with Hemoglobin on Oxidative Modification by Peroxynitrite

Ferryl Hemoglobin and Heme Induce A1-Microglobulin in Hemorrhaged Atherosclerotic Lesions with Inhibitory Function against Hemoglobin and Lipid Oxidation

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