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PubMed: 29544683

Title
Effects of Histidine-rich glycoprotein on erythrocyte aggregation and hemolysis: Implications for a role under septic conditions.
Journal
Journal of pharmacological sciences
Volume
136
Issue
None
Pages
97-106
Date
2018-03-01
Authors
Gao Y | Liu K | Mori S | Nishibori M | Sakaguchi M | Teshigawara K | Wake H | Zhong H

Evidence 139ceeeaa3
JSON

TPEN (20 mM), a chelator for Zn2þ, Fe2þ and Mn2þ, abolished the effects of Zn2þ (Fig. 1A).

a(CHEBI:"N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine") decreases act(a(CHEBI:"zinc(2+)")) View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence 52d16502a6
JSON

The Zn2þ (20 mM)-induced expression of PS on erythrocytes, which was inhibited by TPEN, was not observed by other divalent cations, including Mg2þ and Ca2þ (Fig. 2A).

a(CHEBI:"N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine") decreases act(a(CHEBI:"zinc(2+)")) View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

a(CHEBI:"N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine") decreases a(CHEBI:"phosphatidyl-L-serine") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

a(CHEBI:"zinc(2+)") increases a(CHEBI:"phosphatidyl-L-serine") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence 0ddd13ef41
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TPEN also inhibited erythrocyte adhesion, but the effect at 20 mM was weaker compared to that in the HRG (100 mg/mL)- treatment group.

a(CHEBI:"N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine") decreases a(HM:"erythrocyte-endothelium adhesion") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence 0d27e2a208
JSON

Eryptosis is the apoptotic-like suicidal process of erythrocytes, and is characterized by cell shrinkage and phosphatidylserine (PS) expression on the outer membrane.

a(CHEBI:"phosphatidyl-L-serine") positiveCorrelation bp(MESH:Eryptosis) View Subject | View Object

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MeSH
Erythrocyte Membrane
Text Location
Introduction

bp(MESH:Eryptosis) positiveCorrelation a(CHEBI:"phosphatidyl-L-serine") View Subject | View Object

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MeSH
Erythrocyte Membrane
Text Location
Introduction

Evidence 0f18a0d486
JSON

Stimulation with 20 mM Zn2þ resulted in aggregation of washed human erythrocytes 1 h after incubation.

a(CHEBI:"zinc(2+)") increases bp(MESH:"Erythrocyte Aggregation") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence 127ad756a2
JSON

Thus focusing on Zn2þ-stimulated erythrocytes might be an important new approach that could ultimately reveal the mechanism of immunothrombus formation in sepsis.

a(CHEBI:"zinc(2+)") increases bp(MESH:"Erythrocyte Aggregation") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
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Results

Evidence 892b6e621e
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We found that a considerable number of erythrocytes were attached to the EA.hy926 cells after Zn2þ-stimulation (Fig. 4A).

a(CHEBI:"zinc(2+)") increases a(HM:"erythrocyte-endothelium adhesion") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence 0fbc2f8a9c
JSON

In addition, we observed that Zn2þ induced the adhesion of erythrocytes to endothelial cells, and this effect was not inhibited by 100 mg/mL of HSA (Fig. 4), suggesting a specific interaction between erythrocytes and HRG.

a(CHEBI:"zinc(2+)") increases a(HM:"erythrocyte-endothelium adhesion") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Discussion

Evidence 895be72343
JSON

Although neutrophils, platelets and vascular endothelial cells are the main effector cells involved in immunothrombosis, abnormal aggregation of erythrocytes under septic conditions may also contribute to immunothrombosis in sepsis.

a(HM:Immunothrombosis) positiveCorrelation bp(MESH:"Erythrocyte Aggregation") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Introduction

bp(MESH:"Erythrocyte Aggregation") positiveCorrelation a(HM:Immunothrombosis) View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Introduction

Evidence 61de1d505d
JSON

The cascade of immunothrombosis includes platelet activation and secretion, which may result in a local increase in Zn2þ concentration because of the presence of Zn2þ in platelet dense granules.

a(HM:Immunothrombosis) positiveCorrelation bp(MESH:"Platelet Activation") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

bp(MESH:"Platelet Activation") positiveCorrelation a(HM:Immunothrombosis) View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

bp(MESH:"Platelet Activation") increases a(CHEBI:"zinc(2+)") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence ef856cd7dd
JSON

In 2007, Kempe10 et al. reported that erythrocytes showed an apoptotic tendency in septic patients.

bp(MESH:Eryptosis) positiveCorrelation path(MESH:Sepsis) View Subject | View Object

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MeSH
Erythrocyte Membrane
Text Location
Introduction

path(MESH:Sepsis) positiveCorrelation bp(MESH:Eryptosis) View Subject | View Object

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MeSH
Erythrocyte Membrane
Text Location
Introduction

Evidence cbc69967a8
JSON

HRG strongly inhibited the aggregation at a concentration of 1 mg/mL, whereas the same concentration of HSA showed no effect (Fig. 1B).

p(HGNC:ALB) causesNoChange bp(MESH:"Erythrocyte Aggregation") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

p(HGNC:HRG) decreases bp(MESH:"Erythrocyte Aggregation") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence 6be60de5b7
JSON

HRG and HSA both strongly inhibited aggregation when the concentration was increased to 100 mg/mL (Supplementary Fig. 1).

p(HGNC:ALB) decreases bp(MESH:"Erythrocyte Aggregation") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

p(HGNC:HRG) decreases bp(MESH:"Erythrocyte Aggregation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence 2055d3ec90
JSON

HRG and HSA both inhibited PS expression when their concentrations were increased to 10 and 100 mg/mL (Fig. 2B).

p(HGNC:ALB) decreases a(CHEBI:"phosphatidyl-L-serine") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

p(HGNC:HRG) decreases a(CHEBI:"phosphatidyl-L-serine") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence ad5c8a2474
JSON

HRG treatment significantly inhibited the attachment of erythrocytes to the vascular endothelial cell monolayer in a concentration dependent manner (Fig. 4A and B), while HSA did not affect the adhesion.

p(HGNC:ALB) causesNoChange a(HM:"erythrocyte-endothelium adhesion") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

p(HGNC:HRG) decreases a(HM:"erythrocyte-endothelium adhesion") View Subject | View Object

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Annotations
MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence a6fbaf1ff4
JSON

To determine the role of PS in the Zn2þ-induced aggregation of erythrocytes, we used Annexin V to block PS expression on the erythrocyte membrane.

p(HGNC:ANXA5) decreases a(CHEBI:"phosphatidyl-L-serine") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence a92881bb83
JSON

Annexin V (100 nM) completely inhibited the Zn2þ-induced aggregation (Fig. 1E).

p(HGNC:ANXA5) decreases bp(MESH:"Erythrocyte Aggregation") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence f120d8586c
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The decrease was due to the reduction in HRG gene expression, deposition of HRG on immunothrombi and degradation of HRG by thrombin.

p(HGNC:F2) positiveCorrelation deg(p(HGNC:HRG)) View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Discussion

deg(p(HGNC:HRG)) positiveCorrelation p(HGNC:F2) View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Discussion

Evidence 0b18b53f43
JSON

Surprisingly, HRG at high concentration (100 mg/mL) significantly decreased PS expression on erythrocytes.

p(HGNC:HRG) decreases a(CHEBI:"phosphatidyl-L-serine") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence 56ca856876
JSON

Although a significant difference in PS expressionwas not observed among the CLP groups treated with PBS, HSA or HRG, incubation of erythrocytes for 4 h enabled the observation of beneficial effects of HRG on PS expression on erythrocytes (Fig. 5B).

p(MGI:Hrg) decreases a(CHEBI:"phosphatidyl-L-serine") View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence cd82f6745b
JSON

Hemin-induced hemolysis was also inhibited by HRG and HRGderived peptide (amino acid sequence in the Histidine-rich domain of HRG: HHPHGHHPHG) (Fig. 6A and B).

p(MGI:Hrg) decreases path(MESH:Hemolysis) View Subject | View Object

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MeSH
Erythrocyte Membrane
MeSH
Sepsis
Text Location
Results

Evidence fc94cc4261
JSON

Supplementary treatment of septic mice with purified HRG from human plasma remarkably suppressed immunothrombosis in the lungs as well as the associated inflammation.

p(MGI:Hrg) decreases a(HM:Immunothrombosis) View Subject | View Object

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MeSH
Lung
MeSH
Sepsis
Text Location
Discussion

p(MGI:Hrg) decreases path(MESH:Inflammation) View Subject | View Object

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MeSH
Lung
MeSH
Sepsis
Text Location
Discussion

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