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PubMed: 20378845

Title
Red cells, hemoglobin, heme, iron, and atherogenesis.
Journal
Arteriosclerosis, thrombosis, and vascular biology
Volume
30
Issue
None
Pages
1347-53
Date
2010-07-01
Authors
Vercellotti GM | Nagy E | Balla J | Balla G | Csonka T | Eaton JW | Galajda Z | Jeney V | Méhes G | Smith A | Soares MP | Szentmiklósi J | Varga Z

Evidence df9775f7cb
JSON

Gruel from advanced plaque also contains large amounts of organic soluble carbonyls and aldehydes that are also cytotoxic.

a(CHEBI:"carbonyl group") positiveCorrelation path(MESH:"Plaque, Atherosclerotic") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

a(MESH:Aldehydes) positiveCorrelation path(MESH:"Plaque, Atherosclerotic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

path(MESH:"Plaque, Atherosclerotic") positiveCorrelation a(CHEBI:"carbonyl group") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

path(MESH:"Plaque, Atherosclerotic") positiveCorrelation a(MESH:Aldehydes) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

Evidence 62da01c9ea
JSON

Concentrations of iron, conjugated dienes and lipid hydroperoxides were elevated by about 2- fold in ruptured complicated lesions, as compared to atheromatous lesions (0.433 ± 0.075 vs. 0.185 ± 0.096 nmol Fe/mg tissue; 0.047 ± 0.019 vs. 0.021 ± 0.003 A234 conjugated dienes/mg tissue and 0.465 ± 0.110 vs. 0.248 ± 0.106 nmol LOOH/mg tissue, respectively) and complicated lesions contained 5.6 times more TBARs than atheromatous lesions (0.028 ± 0.012 vs. 0.005 ± 0.001 nmol/mg tissue).

a(CHEBI:"iron(2+)") positiveCorrelation a(HM:"ruptured complicated lesions") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(CHEBI:"lipid hydroperoxide") positiveCorrelation a(HM:"ruptured complicated lesions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"ruptured complicated lesions") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"ruptured complicated lesions") positiveCorrelation a(CHEBI:"lipid hydroperoxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"ruptured complicated lesions") positiveCorrelation a(MESH:"Thiobarbituric Acid Reactive Substances") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(MESH:"Thiobarbituric Acid Reactive Substances") positiveCorrelation a(HM:"ruptured complicated lesions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 14ed547bae
JSON

This engenders the release of iron, which can promote further the oxidation of plaque lipids through redox cycling reactions. The result of these chemical reactions is the formation of deleterious oxidized ‘gruel’ which, among other things, leads to endothelial oxidative stress and ultimately to cytotoxicity.

a(CHEBI:"iron(2+)") positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

bp(MESH:"Oxidative Stress") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

Evidence 5c4cfa25d5
JSON

Earlier chemical investigations of gruel from advanced lesions revealed that it contains ceroid-like insoluble material composed mainly of hydoxyapatite, iron and calcium.

a(CHEBI:"iron(2+)") positiveCorrelation path(MESH:"Plaque, Atherosclerotic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

a(MESH:Calcium) positiveCorrelation path(MESH:"Plaque, Atherosclerotic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

a(MESH:Hydroxyapatites) positiveCorrelation path(MESH:"Plaque, Atherosclerotic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

path(MESH:"Plaque, Atherosclerotic") positiveCorrelation a(MESH:Hydroxyapatites) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

path(MESH:"Plaque, Atherosclerotic") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

path(MESH:"Plaque, Atherosclerotic") positiveCorrelation a(MESH:Calcium) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

Evidence 886d2bec8d
JSON

Hematomas occur in atheromatous lesions and plaque material contains lipid oxidation products including lipid hydroperoxide22 which can mediate not only the oxidation of hemoglobin but might also lyse intact red cells.23

a(CHEBI:"lipid hydroperoxide") increases p(HGNC:HBB, pmod(Ox)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(CHEBI:"lipid hydroperoxide") positiveCorrelation a(HM:"Erythrocytes, lysed") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"Erythrocytes, lysed") positiveCorrelation a(CHEBI:"lipid hydroperoxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

bp(HM:"Atheromatous lesions") positiveCorrelation path(MESH:Hematoma) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Results

path(MESH:Hematoma) positiveCorrelation bp(HM:"Atheromatous lesions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Results

Evidence a2b4f9a284
JSON

Levels of conjugated dienes, lipid hydroperoxides and TBARs were significantly higher in atheromatous lesions compared to controls (supplemental Table I).

a(CHEBI:"lipid hydroperoxide") positiveCorrelation bp(HM:"Atheromatous lesions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(MESH:"Thiobarbituric Acid Reactive Substances") positiveCorrelation bp(HM:"Atheromatous lesions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

bp(HM:"Atheromatous lesions") positiveCorrelation a(CHEBI:"lipid hydroperoxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

bp(HM:"Atheromatous lesions") positiveCorrelation a(MESH:"Thiobarbituric Acid Reactive Substances") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 4c78cc7333
JSON

Moreover, lipids extracted from atheromatous lesions contained 1.9 times more monounsaturated fatty acids than control extracts.

a(CHEBI:"monounsaturated fatty acid") positiveCorrelation a(HM:"Atheroma lipid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"Atheroma lipid") positiveCorrelation a(CHEBI:"monounsaturated fatty acid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence d41eda1392
JSON

In previous studies we found that endothelial cells exposed to oxidized LDL upregulated both heme oxygenase-1 (HO-1) and ferritin,8,9 presumably as a defense mechanism.6,11-14

a(CHEBI:"oxidised LDL") increases p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell

a(CHEBI:"oxidised LDL") increases p(PFAM:Ferritin) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell

Evidence 766b0646b0
JSON

Upregulation of HO-115 and ferritin H chain16 in endothelial cells has been reported in the early phase of progression of atherosclerotic lesions.

a(CHEBI:"oxidised LDL") increases p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis

a(CHEBI:"oxidised LDL") increases p(PFAM:Ferritin) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis

Evidence a78621cc06
JSON

Lipids of atheromatous (Fig 1A, 1b and 2b panels) and ruptured complicated lesions (Fig 1A, 1c and 2c panels) as well as oxidized LDL caused significant lysis of red cells within 24 hours (Fig 1B, black bars).

a(CHEBI:"oxidised LDL") increases a(HM:"Erythrocytes, lysed") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"Atheroma lipid") increases a(HM:"Erythrocytes, lysed") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

bp(HM:"Atheromatous lesions") increases a(HM:"Erythrocytes, lysed") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence fb0f4c7218
JSON

Heme/iron-mediated oxidative modification of LDL can cause endothelial cytotoxicity8,24 and – at sublethal doses – the expression of stress-response genes.9,11-14

a(CHEBI:"oxidised LDL") positiveCorrelation bp(MESH:"Cytotoxicity, Immunologic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

bp(MESH:"Cytotoxicity, Immunologic") positiveCorrelation a(CHEBI:"oxidised LDL") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence e25113463e
JSON

Elevated cholesterol, oxy-cholesterol, lyso-phospholipid and decreased phosphatidylserine were found in atheromatous lipids compared to controls (supplemental Table II).

a(CHEBI:"phosphatidyl-L-serine") negativeCorrelation a(HM:"Atheroma lipid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(CHEBI:cholesterol) positiveCorrelation a(HM:"Atheroma lipid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"Atheroma lipid") positiveCorrelation a(CHEBI:cholesterol) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"Atheroma lipid") positiveCorrelation a(MESH:"5,6-epoxycholesterol") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"Atheroma lipid") negativeCorrelation a(CHEBI:"phosphatidyl-L-serine") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(MESH:"5,6-epoxycholesterol") positiveCorrelation a(HM:"Atheroma lipid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 31818c6d58
JSON

Moreover, the amounts of a protein oxidation marker, dityrosine,21 were elevated in complicated lesions (Fig 5B) whereas atheromatous lesions did not contain detectable dityrosine.

a(CHEBI:dityrosine) positiveCorrelation a(HM:"ruptured complicated lesions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"ruptured complicated lesions") positiveCorrelation a(CHEBI:dityrosine) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 9ce0c9e831
JSON

Previously we have shown that heme can enter the lipid moiety of LDL and induce iron-dependent lipid peroxidation.8

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

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

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

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

Evidence 71704120ea
JSON

Here we demonstrate that lipids isolated from human atheromatous lesions – which are already in an oxidized state – can be further oxidized in the presence of heme, whereas this effect is not observed using lipids isolated from normal vasculature.

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

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

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

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

Evidence aaa762a2bd
JSON

Thus, it appears that these extracts oxidize ferrohemoglobin to ferrihemoglobin, thereby leading to heme instability and heme-mediated initiation of lipid peroxidation.

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

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

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

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

p(HGNC:HBB, pmod(Ox)) positiveCorrelation path(MESH:"Plaque, Atherosclerotic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

path(MESH:"Plaque, Atherosclerotic") positiveCorrelation p(HGNC:HBB, pmod(Ox)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

Evidence 64ba21617f
JSON

Indeed, lipids derived from atheromatous lesions promoted the oxidation of ferrohemoglobin to ferrihemoglobin (Fig 2C).

a(HM:"Atheroma lipid") increases p(HGNC:HBB, pmod(Ox)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence c5b222e373
JSON

Oxysterols and oxidation products of polyunsaturated fatty acids (PUFAs) are present in human atheromatous lesions.4,5

a(CHEBI:oxysterol) positiveCorrelation bp(HM:"Atheromatous lesions") View Subject | View Object

Appears in Networks:

bp(HM:"Atheromatous lesions") positiveCorrelation a(CHEBI:oxysterol) View Subject | View Object

Appears in Networks:

Evidence 62bf861eb9
JSON

As shown in Fig 3B, lipids from atherosclerotic lesions were cytotoxic to endothelium, an effect strikingly enhanced when lipids were pre-oxidized by exposure to heme.

a(HM:"Atheroma lipid") positiveCorrelation path(HM:"Endothelial dysfunction") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

path(HM:"Endothelial dysfunction") positiveCorrelation a(HM:"Atheroma lipid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 51381150cc
JSON

At sublethal doses, atheroma lipid - whether pre-treated with heme or not - induced the expression of the stress-responsive gene HO-1, at both mRNA (Fig 3C) and protein levels (Fig 3D).

a(HM:"Atheroma lipid") increases p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(HM:"Atheroma lipid") increases r(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence e6e9a03857
JSON

We have found that atheroma lipids when oxidized by heme are highly cytotoxic to human endothelial cells, and hemopexin reduced this cytotoxicity.

a(HM:"Atheroma lipid") increases bp(MESH:"Cytotoxicity, Immunologic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

p(HGNC:HPX) decreases path(HM:"Endothelial dysfunction") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

Evidence 4ddf3b4364
JSON

The results reported here indicate that, once exposed to oxidized plaque material, erythrocytes are lysed, the liberated hemoglobin is oxidized and heme dissociates from the resultant ferrihemoglobin.

a(HM:"Erythrocytes, lysed") increases p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

deg(a(HM:ferrihemoglobin)) increases a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

p(HGNC:HBB) increases a(HM:ferrihemoglobin) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

Evidence f23957f6da
JSON

Preincubation of lipid extract derived from atheroma, complicated lesion or oxidized LDL with glutathione/glutathione peroxidase (which specifically reduced lipid hydroperoxide to alcohol by 35%, 38% and 90%, respectively) significantly lowered the lytic effect (Fig 1B, empty bars).Oxidation of liberated hemoglobin was also reduced (Fig 1C, empty bars)

a(MESH:"Glutathione Peroxidase") decreases a(CHEBI:"lipid hydroperoxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(MESH:"Glutathione Peroxidase") decreases a(HM:"Erythrocytes, lysed") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(MESH:"Glutathione Peroxidase") decreases p(HGNC:HBB, pmod(Ox)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 2c12b78b15
JSON

Pre-treatment of heme-oxidized lipids with glutathione/glutathione peroxidase reduced the lipid hydroperoxide content (113±30 vs. 74±22 nmol LOOH/mg extract, p<0.01) and inhibited the endothelial cell cytotoxicity by 25% (p<0.05).

a(MESH:"Glutathione Peroxidase") decreases a(CHEBI:"lipid hydroperoxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

a(MESH:"Glutathione Peroxidase") decreases bp(MESH:"Cytotoxicity, Immunologic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 62c4513d87
JSON

Furthermore, the induction of HO-1 was decreased (153 ± 16 versus 105 ± 3 pmol bilirubin formed per milligram of cell protein per 60 minutes, p<0.01) in endothelial cells.

a(MESH:"Glutathione Peroxidase") decreases p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 1935010ac4
JSON

We recently found that, contrary to other forms of oxidized hemoglobin, ferrylhemoglobin acts as a potent pro-inflammatory agonist in endothelial cells, leading to the up-regulation of adhesion molecules that support the recruitment of macrophages into the vessel wall.36

a(MESH:ferrylhemoglobin) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

a(MESH:ferrylhemoglobin) increases a(MESH:"Cell Adhesion Molecules") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

path(MESH:Inflammation) positiveCorrelation a(MESH:ferrylhemoglobin) View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

Evidence 6dbc73659f
JSON

Atheromatous lesions are prone to disruption leading to hematoma or hemorrhage.

bp(HM:"Atheromatous lesions") positiveCorrelation path(MESH:Hematoma) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

bp(HM:"Atheromatous lesions") positiveCorrelation path(MESH:Hemorrhage) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

path(MESH:Hematoma) positiveCorrelation bp(HM:"Atheromatous lesions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

path(MESH:Hemorrhage) positiveCorrelation bp(HM:"Atheromatous lesions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

Evidence 581403b93a
JSON

Elevated amounts of HO-1 were found in macrophages and medial smooth muscle cells of human atherosclerotic lesions.15

bp(HM:"Atheromatous lesions") positiveCorrelation p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

p(HGNC:HMOX1) positiveCorrelation bp(HM:"Atheromatous lesions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

Evidence ae6de7a3b0
JSON

Inhibition of lipid oxidation by either haptoglobin or hemopexin reduced the cytotoxicity (Fig 4B) and HO-1 induction caused by sublethal amounts of pretreated atheromatous lesion lipids (Fig 4C and D).

bp(MESH:"Cytotoxicity, Immunologic") positiveCorrelation bp(MESH:"Lipid Peroxidation") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

bp(MESH:"Lipid Peroxidation") positiveCorrelation bp(MESH:"Cytotoxicity, Immunologic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

p(HGNC:HPX) decreases bp(MESH:"Lipid Peroxidation") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

p(HGNC:HP) decreases bp(MESH:"Lipid Peroxidation") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence e938acbb96
JSON

Treatment of oxidized LDL (Fig 2B), or atheroma lipids (Fig 2D) with glutathione/glutathione peroxidase lowered the lipid hydroperoxide content as well as the oxidation of hemoglobin.

complex(a(CHEBI:"oxidised LDL"), a(MESH:"Glutathione Peroxidase")) decreases a(CHEBI:"lipid hydroperoxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

complex(a(CHEBI:"oxidised LDL"), a(MESH:"Glutathione Peroxidase")) decreases p(HGNC:HBB, pmod(Ox)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence eda2b0acf5
JSON

As is true of intact hemoglobin, lipid extracts from atheromatous lesions exposed to heme also underwent lipid peroxidation as reflected by the accumulation of thiobarbituric acid-reactive substances (TBARs) and lipid hydroperoxides (supplemental Fig I).

complex(a(CHEBI:heme), a(HM:"Atheroma lipid")) increases a(MESH:"Thiobarbituric Acid Reactive Substances") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

complex(a(CHEBI:heme), a(HM:"Atheroma lipid")) increases a(CHEBI:"lipid hydroperoxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

complex(a(CHEBI:heme), a(HM:"Atheroma lipid")) increases bp(MESH:"Lipid Peroxidation") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence b20138f881
JSON

Now we demonstrate that heme and hemoglobin-treated atheroma lipids also induce HO-1 in endothelial cells exposed in sublethal doses.

complex(a(CHEBI:heme), a(HM:"Atheroma lipid")) increases p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

complex(a(HM:"Atheroma lipid"), p(HGNC:HBB)) increases p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Atherosclerosis
Text Location
Discussion

Evidence 4148718b58
JSON

This serum protein, present at remarkably high concentrations in plasma (≈1g/L), binds heme with extraordinary avidity (Kd less than 1 pmol/ L) and promotes its clearance.

complex(a(CHEBI:heme), p(HGNC:HPX)) increases deg(a(CHEBI:heme)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

Evidence d597bf1486
JSON

Moreover, the heme-binding protein, hemopexin, also suppressed the oxidation of lipid by ferro- and ferrihemoglobin, indicating the necessity for heme release from ferrihemoglobin for this oxidative process.

p(HGNC:HPX) decreases a(HM:"oxidative modification of atheroma lipid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 76674931fa
JSON

Both the hemoglobin-binding protein, haptoglobin,27 and the heme-binding protein, hemopexin, inhibited such oxidative modification of lipids indicating the importance of heme loss and scission in hemoglobin-provoked oxidation of lipids derived from atheromatous lesions.

p(HGNC:HPX) decreases a(HM:"oxidative modification of atheroma lipid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

p(HGNC:HP) decreases a(HM:"oxidative modification of atheroma lipid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

Evidence 23a835701a
JSON

The heme-binding protein, hemopexin, which likely prevents heme:lipid interactions and blocks the oxidative scission of heme,26 significantly inhibited the oxidative reactions.

p(HGNC:HPX) decreases a(HM:"oxidative reactions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

Evidence 60e81c5d6a
JSON

Hemoglobinmediated oxidative modification of lipid extracted from atheromatous lesions was inhibited by haptoglobin (Fig 4A).

p(HGNC:HP) decreases a(HM:"oxidative modification of atheroma lipid") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Results

Evidence 51a5579099
JSON

Expression of HO-1 provides protection against atherosclerosis in several experimental models17,18 and HO-1 deficiency in humans has been associated with the appearance of vasculature fatty streaks and atheromatous plaques at age of six.19

p(HGNC:HMOX1) negativeCorrelation path(MESH:Atherosclerosis) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis

p(HGNC:HMOX1) negativeCorrelation path(MESH:"Plaque, Atherosclerotic") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis

path(MESH:"Plaque, Atherosclerotic") negativeCorrelation p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis

path(MESH:Atherosclerosis) negativeCorrelation p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis

Evidence 4ef91db2ea
JSON

Heme oxygenase-1, a key antioxidant enzyme that exerts cytoprotective effects in endothelial cells8,11-14 also plays an important role in preventing the development of atherosclerosis.

p(HGNC:HMOX1) negativeCorrelation path(HP:atherosclerosis) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

path(HP:atherosclerosis) negativeCorrelation p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Atherosclerosis
Text Location
Discussion

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.