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PubMed: 19276082

Title
Erythrocyte hemolysis and hemoglobin oxidation promote ferric chloride-induced vascular injury.
Journal
The Journal of biological chemistry
Volume
284
Issue
None
Pages
13110-8
Date
2009-05-08
Authors
Chin-Dusting JP | Jackson SP | Salem HH | Sturgeon S | Woollard KJ

Evidence fd5413edb4
JSON

By-products of heme and iron metabolism, such as heme oxygenase-dependent generation of carbon monoxide (CO), have antioxidant and anti-inflammatory protective functions against iron-induced vascular damage (33); therefore we examined the impact of CO donors on collagen exposure and thrombus formation in the ex vivo vascular injury model.

a(CHEBI:"carbon monoxide") negativeCorrelation path(MESH:"Vascular System Injuries") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

path(MESH:"Vascular System Injuries") negativeCorrelation a(CHEBI:"carbon monoxide") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

Evidence e9d8490e69
JSON

Pretreating anticoagulated whole blood with tricarbonyldichlororuthenium(II) dimer, a CO donor, significantly reduced collagen exposure (Fig. 5A) and thrombus formation (Fig. 5B) induced by FeCl3.

a(CHEBI:"carbon monoxide") negativeCorrelation a(HM:Thrombus) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

a(CHEBI:"iron trichloride") positiveCorrelation a(HM:Thrombus) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

a(HM:Thrombus) negativeCorrelation a(CHEBI:"carbon monoxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

a(HM:Thrombus) positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

Evidence 782be71210
JSON

High concentrations of FeCl3 induce profound injury to the vasculature, leading to endothelial denudation, and collagen and tissue factor exposure, leading to the rapid formation of vaso-occlusive thrombi.

a(CHEBI:"iron trichloride") positiveCorrelation path(MESH:"Vascular System Injuries") View Subject | View Object

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Introduction

path(MESH:"Vascular System Injuries") positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

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Introduction

Evidence 34dbe7a8e9
JSON

As demonstrated in Fig. 1, topically exposing aorta in vivo (Fig. 1A) or ex vivo (Fig. 1B) to 6% FeCl3 resulted in major vascular injury as evidenced by endothelial denudation, collagen exposure, and the subsequent formation of arterial thrombi (Fig. 1D and supplemental Video 1).

a(CHEBI:"iron trichloride") positiveCorrelation path(MESH:"Vascular System Injuries") View Subject | View Object

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Introduction

path(MESH:"Vascular System Injuries") positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

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Introduction

Evidence 3531271182
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Analysis of the time course of hemolysis in whole blood revealed a rapid linear increase in Hb levels, peaking 10 min after FeCl3 addition (Fig. 2B), a time course consistent with the rapid hemolysis and vascular injury observed in the ex vivo aortic thrombosis model.

a(CHEBI:"iron trichloride") positiveCorrelation path(MESH:"Vascular System Injuries") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

a(CHEBI:"iron trichloride") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

a(CHEBI:"iron trichloride") positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

path(MESH:"Vascular System Injuries") positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

path(MESH:Hemolysis) positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

Evidence a3a4527f75
JSON

To investigate the direct effects of FeCl3 on aortic endothelium, FeCl3 was perfused through isolated aorta independently of flowing blood. Strikingly no endothelial denudation or collagen exposure was evident following prolonged exposure to FeCl3 (6%) (Fig. 1C).

a(CHEBI:"iron trichloride") negativeCorrelation path(HM:"Endothelial dysfunction") View Subject | View Object

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Cell Ontology (CL)
platelet
MeSH
Aorta
Text Location
Introduction

path(HM:"Endothelial dysfunction") negativeCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

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Cell Ontology (CL)
platelet
MeSH
Aorta
Text Location
Introduction

Evidence 547d80ab7f
JSON

Subsequent perfusion of anticoagulated whole blood through FeCl3-pretreated vessels was associated with an increase in leukocyte and platelet adhesion to the vessel wall (Fig. 1E and supplemental Video 2); however, relative to untreated aorta (Fig. 1F and supplemental Video 3) and treatment in the presence of flowing blood (Fig. 1D and supplemental Video 1), thrombus formation was not observed.

a(CHEBI:"iron trichloride") positiveCorrelation path(HM:"Endothelial dysfunction") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
platelet
MeSH
Blood
Text Location
Introduction

a(CHEBI:"iron trichloride") positiveCorrelation bp(GO:"leukocyte adhesion to vascular endothelial cell") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
platelet
MeSH
Blood
Text Location
Introduction

a(CHEBI:"iron trichloride") positiveCorrelation bp(MESH:"Platelet Adhesiveness") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
platelet
MeSH
Blood
Text Location
Introduction

bp(GO:"leukocyte adhesion to vascular endothelial cell") positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
platelet
MeSH
Blood
Text Location
Introduction

bp(MESH:"Platelet Adhesiveness") positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
platelet
MeSH
Blood
Text Location
Introduction

path(HM:"Endothelial dysfunction") positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

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Cell Ontology (CL)
platelet
MeSH
Blood
Text Location
Introduction

Evidence 63fd009fc5
JSON

In contrast, selectively removing RBCs prevented endothelial denudation and collagen exposure, resulting in a relatively mild perturbation of endothelial function similar to that observed with FeCl3 alone (data not shown).

a(CHEBI:"iron trichloride") positiveCorrelation path(HM:"Endothelial dysfunction") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Blood
Text Location
Introduction

path(HM:"Endothelial dysfunction") positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Blood
Text Location
Introduction

Evidence ee70dc49e2
JSON

Analysis of Hb release from ex vivo vessel chamber experiments revealed a significant (p  0.05; n  4) increase in Hb levels following FeCl3 treatment of isolated aorta in the presence of flowing blood (157  45 g/ml), whereas FeCl3 pretreatment of vessels prior to blood perfusion caused no hemolysis (Fig. 2A).

a(CHEBI:"iron trichloride") positiveCorrelation p(HGNC:HBB) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

Evidence 1ae5c4f2ce
JSON

FeCl3 treatment resulted in a dose- (Fig. 3) and timedependent (data not shown) increase inRBClipid peroxidation, which correlated closely with hemolysis (Fig. 2B).

a(CHEBI:"iron trichloride") positiveCorrelation bp(MESH:"Lipid Peroxidation") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

bp(MESH:"Lipid Peroxidation") positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

Evidence 1f95f3eaed
JSON

Interestingly elevated levels of body iron stores are associated with an increased risk of myocardial infarction, and carriers of the hemochromatosis gene have an increased risk of myocardial infarction and cardiovascular death (20, 21).

a(CHEBI:"iron(2+)") positiveCorrelation path(HP:"Myocardial infarction") View Subject | View Object

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path(HP:"Myocardial infarction") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Evidence 6645229ee7
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Free heme is lipophilic and intercalates into the membrane of endothelial cells increasing vascular permeability and ICAM-1, VCAM-1, and E-selectin expression (19).

a(CHEBI:heme) positiveCorrelation bp(GO:"regulation of vascular permeability") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

a(CHEBI:heme) positiveCorrelation p(MGI:Icam1) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

a(CHEBI:heme) positiveCorrelation p(MGI:Vcam1) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

a(CHEBI:heme) positiveCorrelation p(MGI:Sele) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

bp(GO:"regulation of vascular permeability") positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

p(MGI:Icam1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

p(MGI:Sele) positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

p(MGI:Vcam1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

Evidence b512e90f2b
JSON

As a consequence, infused heme (hemin) has been demonstrated to enhance leukocyte adhesion to the vessel wall (17, 18), a finding confirmed in the current study.

a(CHEBI:heme) positiveCorrelation bp(GO:"leukocyte adhesion to vascular endothelial cell") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

bp(GO:"leukocyte adhesion to vascular endothelial cell") positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

Evidence 924d833a4c
JSON

Platelet thrombus formation in the ex vivo model occurred in the presence of hirudin (Fig. 1B); however, it was critically dependent on collagen activation of platelets as thrombus formation failed to develop using platelets deficient in the major collagen receptor GPVI/FcR -chain (FcR / mice) (data not shown).

a(HM:Thrombus) positiveCorrelation p(MGI:Gp6) View Subject | View Object

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Cell Ontology (CL)
platelet
Text Location
Introduction

p(MGI:Gp6) positiveCorrelation a(HM:Thrombus) View Subject | View Object

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Cell Ontology (CL)
platelet
Text Location
Introduction

Evidence 3d0c9ec6ad
JSON

Moreover they have demonstrated that released Hb plays an important role in exacerbating RBC hemolysis, establishing a damaging hemolysis/ oxidative cycle that drives further red cell damage, vascular injury, and thrombosis.

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

path(MESH:"Vascular System Injuries") positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

path(MESH:Hemolysis) positiveCorrelation path(MESH:"Vascular System Injuries") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

path(MESH:Hemolysis) positiveCorrelation path(MESH:Thrombosis) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

path(MESH:Thrombosis) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

Evidence c48079f23a
JSON

Topical treatment with 6% FeCl3 with hemin (1mM) perfusions caused no greater endothelial injury than FeCl3 or hemin (1 mM) alone (data not shown), whereas FeCl3 in the presence of low concentrations of metHb (0.38 mg/ml) induced extensive vascular injury similar to that observed with FeCl3 in the presence of whole blood (Figs. 4 and 1D, respectively).

complex(a(CHEBI:"iron trichloride"), a(CHEBI:methemoglobin)) positiveCorrelation path(HM:"Endothelial dysfunction") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

path(HM:"Endothelial dysfunction") positiveCorrelation complex(a(CHEBI:"iron trichloride"), a(CHEBI:methemoglobin)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

Evidence 9504c2eed0
JSON

Third, reintroduction of washed RBCs or purified metHb in the presence of FeCl3 led to a similar level of vascular injury as observed with whole blood, whereas isolated RBC membranes and heme, even in the presence of FeCl3, produced relatively mild injury.

complex(a(CHEBI:"iron trichloride"), a(CHEBI:methemoglobin)) positiveCorrelation path(HM:"Endothelial dysfunction") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

path(HM:"Endothelial dysfunction") positiveCorrelation complex(a(CHEBI:"iron trichloride"), a(CHEBI:methemoglobin)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

Evidence 4c1b862db1
JSON

Clinical studies have confirmed endothelial dysfunction and vasculopathy in a patient with HO-1 deficiency, and similarly, mice lacking HO-1 have increased vascular injury and thrombotic complications (43, 44).

p(MGI:Hmox1) negativeCorrelation path(MESH:"Vascular System Injuries") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

p(MGI:Hmox1) negativeCorrelation path(MESH:Thrombosis) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

path(MESH:"Vascular System Injuries") negativeCorrelation p(MGI:Hmox1) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

path(MESH:Thrombosis) negativeCorrelation p(MGI:Hmox1) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

Evidence b0049e73f0
JSON

Furthermore superoxide can react with Hb to produce hydrogen peroxide (H2O2), a well defined prooxidative molecule that causes vascular injury (1).

path(MESH:"Vascular System Injuries") positiveCorrelation rxn(reactants(a(CHEBI:superoxide), p(HGNC:HBB)), products(a(CHEBI:"hydrogen peroxide"))) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

rxn(reactants(a(CHEBI:superoxide), p(HGNC:HBB)), products(a(CHEBI:"hydrogen peroxide"))) positiveCorrelation path(MESH:"Vascular System Injuries") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

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