Heme as a Target for Therapeutic Interventions

Immenschuh, Stephan; Vijayan, Vijith; Janciauskiene, Sabina; Gueler, Faikah

doi:10.3389/fphar.2017.00146

Cited by 100 publications

(109 citation statements)

References 195 publications

(235 reference statements)

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“…1A), which is consistent with previous reports that excess free heme is toxic via pro-oxidant, cytotoxic and proin ammatory effects [27]. In mammals, heme homeostasis can be maintained by hemopexin neutralization or HO-1 enzymatic hydrolysis of excess free heme, 30 µM heme can accumulate in mitochondria that synthesize heme [28], while in hemolytic diseases vascular endothelial cells may encounter up to 100 µM concentration of heme and open a selfprotective mechanism [25], suggesting that 20 µM heme is safe in dose, it was reported in Nature that heme at a dose of 50 mg/kg could speci cally degrade BACH1 in mice without affecting normal physiological functions [9]. Therefore, for the rst time, we attempted to use 20 µM heme to speci cally inhibit BACH1 expression in vascular endothelial cells, and observed that this effect could promote VEGF expression in vascular endothelial cells.…”

Section: Discussionsupporting

confidence: 89%

“…Heme is a complex of iron and the tetrapyrrole protoporphyrin IX with essential functions in aerobic organisms, participate in biological oxygen transport, respiratory chain electron transfer, etc. It can be degraded to iron, carbon monoxide and biliverdin by HO-1, which has anti-in ammatory, antioxidant and anti-apoptotic effects [25]. It has been used in the treatment of porphyria hepatica, it is a safe and reliable drug, which can be orally and intravenously injected [26], more convenient and safer than intravitreal injection.…”

Section: Discussionmentioning

confidence: 99%

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Heme relieves the inhibition of proliferation, migration and angiogenesis of HMEC-1 under hyperoxia by inhibiting BACH1

Jian¹,

Mei²,

Yuan³

2020

Preprint

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Background The relatively hyperoxia inhibited vascular endothelial growth factor (VEGF) in retina is the main cause of angiogenesis retardation in phase I retinopathy of prematurity (ROP). Human retinal angiogenesis is related to the proliferation, migration and angiogenesis of microvascular endothelial cells. Previous studies have confirmed that BTB and CNC homology l (BACH1) can inhibit VEGF and angiogenesis, while heme can specifically degrade BACH1. However, the effect of heme on endothelial cells and ROP remains unknown. Methods In this report, we established a model of human microvascular endothelial cells (HMEC-1) induced by 40% hyperoxia to simulate the relatively hyperoxia of phase I ROP. Meanwhile, heme was added to investigate the effects on the growth and viability of HMEC-1. Cell counting kit 8 (CCK8) and 5-ethynyl-2′-deox-yuridine (EDU) methods were used to detect the proliferation ability. Cell scratch test and matrigel matrix glue were used to detect the migration or angiogenesis ability. Western blot and immunofluorescence methods were used to detect the relative protein expression of BACH1 and VEGF. Results The proliferation, migration and angiogenesis of HMEC-1 were inhibited under hyperoxia. Moderate heme can promote endothelial cell proliferation, while excessive can inhibit, 20 µM heme could inhibit the expression of BACH1, promote the expression of VEGF, and relieve the inhibition of proliferation, migration and angiogenesis induced by hyperoxia in HMEC-1. Conclusions 20 µM heme can relieve the inhibitory effects induced by hyperoxia, via the mechanism of promoting VEGF by inhibiting BACH1 in HMEC-1, and maybe a potential medicine for retinal angiogenesis retardation induced by relatively hyperoxia in phase I ROP.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Heme relieves the inhibition of proliferation, migration and angiogenesis of HMEC-1 under hyperoxia by inhibiting BACH1

Jian¹,

Mei²,

Yuan³

2020

Preprint

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“…Surface plasmon resonance analysis indicated that the dissociation constant (K D ) and binding number for Bach1HBR-C WT with heme are 1.37 × 10 -5 M and 2.3, respectively. The dissociation constant represents a relatively low affinity, and other heme-binding proteins exhibit K D values from 1 × 10 -6 M (α1-microglobulin) to 1 × 10 -14 M (hemopexin) (Immenschuh et al 2017). In our previous report, we found the K D value for Bach2 with heme to be 1.67 × 10 -7 M (Suenaga et al 2016).…”

Section: Heme Binds To the Cp Motifmentioning

confidence: 88%

Functional Heme Binding to the Intrinsically Disordered C-Terminal Region of Bach1, a Transcriptional Repressor

Segawa

Watanabe-Matsui

Matsui

et al. 2019

Tohoku J. Exp. Med.

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Heme is one of the key factors involved in the oxidative stress response of cells. The transcriptional repressor Bach1 plays an important role in this response through its heme-binding activity. Heme inhibits the transcriptional-repressor activity of Bach1, and can occur in two binding modes: 5-and 6-coordinated binding. The Cys-Pro (CP) motif has been determined to be the heme-binding motif of Bach family proteins. The sequence of Bach1 includes six CP motifs, and four CP motifs are functional. With the aim of elucidating the molecular mechanism of heme-Bach1 regulation, we conducted biophysical analyses focusing on the C-terminal region of mouse Bach1 (residues 631-739) which is located after the bZip domain and includes one functional CP motif. UV-Vis spectroscopy indicated that the CP motif binds heme via 5-coordinated bond. A mutant, which included a cysteine to alanine substitution at the CP motif, did not show 5-coordination, suggesting that this binding mode is specific to the CP motif. Surface plasmon resonance revealed that the binding affinity and stoichiometry of heme with the Bach1 C-terminal region were K D = 1.37 × 10 -5 M and 2.3, respectively. The circular dichroism spectrum in the near-UV region exhibited peaks for heme binding to the CP motif. No significant spectral shifts were observed in the far-UV region when samples with and without heme were compared. Therefore, disordered-ordered transition such as "coupled folding and binding" is not involved in the Bach1-heme system. Consequently, the heme response of this C-terminal region is accomplished by disorder-disorder conformational alteration.

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“…Hemopexin is a scavenger protein of haemoglobin and a predominant heme binding protein, which contributes to heme homeostasis (Smith and McCulloh, 2015;Immenschuh et al, 2017). Hemopexin also associates with high density lipoproteins (HDL), influencing their inflammatory properties (Mehta and Reddy, 2015).…”

Section: Discussionmentioning

confidence: 99%

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Criscitiello

Kraev

Lange

2020

Molecular Immunology

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A B S T R A C TPeptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes which posttranslationally convert arginine into citrulline in target proteins in an irreversible manner, causing functional and structural changes in target proteins. Protein deimination causes generation of neo-epitopes, affects gene regulation and also allows for protein moonlighting. Furthermore, PADs have been found to be a phylogenetically conserved regulator for extracellular vesicle (EVs) release. EVs are found in most body fluids and participate in cellular communication via transfer of cargo proteins and genetic material. In this study, post-translationally deiminated proteins in serum and serum-EVs are described for the first time in camelids, using the llama (Lama glama L. 1758) as a model animal. We report a poly-dispersed population of llama serum EVs, positive for phylogenetically conserved EV-specific markers and characterised by TEM. In serum, 103 deiminated proteins were overall identified, including key immune and metabolic mediators including complement components, immunoglobulin-based nanobodies, adiponectin and heat shock proteins. In serum, 60 deiminated proteins were identified that were not in EVs, and 25 deiminated proteins were found to be unique to EVs, with 43 shared deiminated protein hits between both serum and EVs. Deiminated histone H3, a marker of neutrophil extracellular trap formation, was also detected in llama serum. PAD homologues were identified in llama serum by Western blotting, via cross reaction with human PAD antibodies, and detected at an expected 70 kDa size. This is the first report of deiminated proteins in serum and EVs of a camelid species, highlighting a hitherto unrecognized post-translational modification in key immune and metabolic proteins in camelids, which may be translatable to and inform a range of human metabolic and inflammatory pathologies.

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Heme as a Target for Therapeutic Interventions

Cited by 100 publications

References 195 publications

Heme relieves the inhibition of proliferation, migration and angiogenesis of HMEC-1 under hyperoxia by inhibiting BACH1

Heme relieves the inhibition of proliferation, migration and angiogenesis of HMEC-1 under hyperoxia by inhibiting BACH1

Functional Heme Binding to the Intrinsically Disordered C-Terminal Region of Bach1, a Transcriptional Repressor

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

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