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PubMed: 28314763

Title
Endothelial dysfunction inhibits the ability of haptoglobin to prevent hemoglobin-induced hypertension.
Journal
American journal of physiology. Heart and circulatory physiology
Volume
312
Issue
None
Pages
H1120-H1127
Date
2017-06-01
Authors
Bloch DB | Buys ES | Graw JA | Rezoagli E | Warren HS | Yu B | Zapol WM

Evidence 9d87fa0689
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The extensive crosslinkage of cell-free hemoglobin in a high-molecular weight HBOC retains cell-free hemoglobin dimers in the intravascular compartment, thereby preventing extravasation 112 of cell-free hemoglobin into the muscular layer of the arteries where local NO consumption can trigger vasoconstriction (25).

a(CHEBI:"nitric oxide") increases bp(GO:vasoconstriction) View Subject | View Object

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Evidence dfd6a5815d
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Increased plasma concentrations of cell-free heme, the breakdown product of 390 hemoglobin, promote activation and inflammation of endothelial cells and enhance 391 oxidative stress and vascular permeability (22).

a(CHEBI:heme) increases path(MESH:Inflammation) View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
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Introduction

a(CHEBI:heme) increases bp(GO:"endothelial cell activation") View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
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Introduction

a(CHEBI:heme) increases bp(MESH:"Oxidative Stress") View Subject | View Object

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Cell Ontology (CL)
endothelial cell
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Arteries
MeSH
Diabetes Mellitus
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Evidence b8e81c7909
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Some of the adverse effects caused by cell-free hemoglobin are a result of depletion of nitric oxide (NO), which may lead to vasoconstriction, inflammation, and platelet activation (10, 24).

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

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Evidence 2f6e1b3961
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Compared to wild-type (WT) mice, mice with 117 endothelial dysfunction have an increased vasoconstrictor response to infusion of 118 cell-free hemoglobin (25).

p(HGNC:HBB) increases path(HM:"Endothelial dysfunction") View Subject | View Object

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Evidence 38ebd7af6a
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These data suggest that co-administration of human haptoglobin or hemopexin does 276 not attenuate the conversion of NO to nitrate that is mediated by cell-free murine 277 hemoglobin.

p(HGNC:HBB) increases rxn(reactants(a(CHEBI:"nitric oxide")), products(a(CHEBI:nitrate))) View Subject | View Object

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Evidence 28b4411753
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SBP 315 increased 27±2 mmHg during the 40 minutes following infusion of hemoglobin in 316 db/db mice (Figure 4A).

p(HGNC:HBB) increases bp(MESH:"Blood Pressure") View Subject | View Object

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MeSH
Diabetes Mellitus
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Introduction

Evidence cd0dae7f87
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Previous studies showed that db/db mice have enhanced 312 susceptibility to hemoglobin-induced vasoconstriction (25).

p(HGNC:HBB) increases bp(GO:vasoconstriction) View Subject | View Object

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Diabetes Mellitus
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Introduction

Evidence 8bc7328660
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Intravenous infusion of cell-free hemoglobin induces hypertension in mice 205 (24).

p(HGNC:HBB) increases path(MESH:Hypertension) View Subject | View Object

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Evidence f015d3ad9d
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When mice 347 are infused with extracellular hemoglobin that has been extensively crosslinked and 348 only contains a small fraction of monomeric hemoglobin (as in the HBOCs, 349 PolyHeme), scavenging of NO is markedly reduced (25).

p(HGNC:HBB) decreases a(HM:"Nitric oxide scavenging") View Subject | View Object

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Diabetes Mellitus
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Evidence 158018a241
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Inhibition of extravasation of cross-linked extracellular 352 hemoglobin has been postulated as a possible mechanism of decreased NO353 scavenging in the muscular layer of arteries by high-molecular weight HBOCs.

p(HGNC:HBB) decreases a(HM:"Nitric oxide scavenging") View Subject | View Object

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Diabetes Mellitus
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Evidence 52a08b1284
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The mechanism postulated for the beneficial effects 398 of hemopexin in mouse models of chronic hemolysis involves inhibition of heme399 dependent activation of TLR4 signaling and a combination of reduced endothelial 400 formation of reactive oxygen species and restored endothelial NOS-activity.

p(MGI:Hpx) decreases p(MGI:Tlr4) View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
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Introduction

Evidence 46e9d32263
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These results show that, in contrast to haptoglobin, hemopexin 247 was unable to prevent free hemoglobin-induced hemoglobinuria.

p(MGI:Hpx) increases path(MESH:Hemoglobinuria) View Subject | View Object

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Evidence 120ce73dd6
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In mouse models associated with 392 chronic hemolysis and heme overload, such as in mice with a sickle hemoglobin 393 (HbS) gene knock-in or mouse models of β-thalassemia, repeated treatment with 394 hemopexin was shown to reduce chronically elevated blood pressure (21).

p(MGI:Hpx) decreases bp(MESH:"Blood Pressure") View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
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Introduction

Evidence 72de6c8ae9
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TLR4 401 activation by free heme would induce mobilization of P-selectin and von Willebrand 402 factor to the endothelial surface that triggers VCAM-1, ICAM-1, and E-selectin403 dependent hemostasis and vasoocclusion (3, 4).

p(MGI:Tlr4) increases p(MGI:Vcam1) View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
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p(MGI:Tlr4) increases p(MGI:Icam1) View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
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p(MGI:Tlr4) increases p(MGI:Sele) View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
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Introduction

Evidence c632882ebf
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Likewise, 395 infusion of haptoglobin or hemopexin in HbS mice inhibited hemoglobin-dependent 396 vaso-occlusion (3).

p(MGI:Hp) decreases path(HM:"vaso-occlusive crisis") View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Arteries
MeSH
Diabetes Mellitus
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Introduction

Evidence b10153f9c0
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By binding cell-free hemoglobin, haptoglobin prevents glomerular filtration of cell-free hemoglobin and subsequent kidney injury (2,7).

p(MGI:Hp) decreases path(MESH:"Acute Kidney Injury") View Subject | View Object

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Evidence f0f87fdd89
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Schaer and colleagues 107 showed that administration of exogenous haptoglobin prevents extravasation of cell free hemoglobin and vasoconstriction in rats (18).

p(MGI:Hp) decreases bp(GO:vasoconstriction) View Subject | View Object

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Evidence 4f03049bce
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Furthermore, haptoglobin retained cell-free 338 hemoglobin in plasma and prevented hemoglobinuria.

p(MGI:Hp) decreases path(MESH:Hemoglobinuria) View Subject | View Object

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MeSH
Diabetes Mellitus
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Introduction

Evidence 39b7d0c14b
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In mice fed a HFD or in 339 diabetic mice fed a normal diet, haptoglobin mixed with murine tetrameric 340 hemoglobin in a 1:1 weight ratio also retained cell-free hemoglobin in plasma and 341 prevented hemoglobinuria but did not reduce hemoglobin-induced hypertension.

p(MGI:Hp) decreases path(MESH:Hemoglobinuria) View Subject | View Object

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Diabetes Mellitus
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Evidence 87ccf09f71
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In the 358 current study, we demonstrated that administration of human haptoglobin retained 359 cell-free hemoglobin in plasma, prevented hemoglobinuria, and reduced the 360 hemoglobin-induced hypertension in healthy awake mice (see Figure 1A).

p(MGI:Hp) decreases path(MESH:Hemoglobinuria) View Subject | View Object

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MeSH
Diabetes Mellitus
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p(MGI:Hp) decreases path(MESH:Hypertension) View Subject | View Object

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Diabetes Mellitus
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Evidence 9412f1c5ed
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Recent data suggest that haptoglobin prevents hemoglobin-induced hypertension by 355 a similar mechanism (18).

p(MGI:Hp) decreases path(MESH:Hypertension) View Subject | View Object

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Diabetes Mellitus
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Evidence 0b72a6dc4c
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Haptoglobin binds to hemoglobin dimers and forms a high-molecular weight haptoglobin-hemoglobin complex, which is cleared from the circulation after binding to the CD163 receptor on hepatic and splenic macrophages (12).

p(HGNC:CD163) increases deg(a(MESH:"haptoglobin-hemoglobin complex")) View Subject | View Object

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Evidence e8db4aa6bc
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Co-administration of haptoglobin attenuated the hemoglobin-induced increase in SBP during the 40 minutes after co-injection by an average of 13±3 mmHg (Figure 1A).

complex(p(HGNC:HBB), p(MGI:Hp)) decreases bp(MESH:"Blood Pressure") View Subject | View Object

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Evidence a4fd8d5d16
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These results 230 suggest that co-injection of haptoglobin but not hemopexin with cell-free hemoglobin 231 can prevent hemoglobin-induced hypertension in awake, healthy mice.

complex(p(HGNC:HBB), p(MGI:Hp)) decreases path(MESH:Hypertension) View Subject | View Object

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Evidence 4961f4bb75
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Haptoglobin binds to cell-free hemoglobin and thereby prevents glomerular filtration 237 (6).

complex(p(HGNC:HBB), p(MGI:Hp)) decreases bp(MESH:"Glomerular Filtration Rate") View Subject | View Object

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Evidence 9a028f22dd
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Mice that received cell free hemoglobin together with haptoglobin had significantly higher plasma NO 258 consumption than mice that received cell-free hemoglobin alone at 60 minutes after 259 injection.

complex(p(HGNC:HBB), p(MGI:Hp)) increases a(HM:"nitric oxide consumption") View Subject | View Object

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Evidence 15beb5b605
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Taken together these results suggest that infusion of cell-free hemoglobin 264 mixed with an equal mass of haptoglobin is sufficient to bind cell-free hemoglobin 265 and prevent renal clearance of extracellular hemoglobin.

complex(p(HGNC:HBB), p(MGI:Hp)) decreases path(MESH:Hemoglobinuria) View Subject | View Object

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Evidence b23a0443fb
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SBP increased 224 on average 20±2 mmHg in mice injected with hemoglobin mixed with hemopexin and 225 therefore was similar to the increase after hemoglobin injection alone.

complex(p(HGNC:HBB), p(MGI:Hpx)) increases bp(MESH:"Blood Pressure") View Subject | View Object

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Evidence 2c12c829be
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Mice with diabetes mellitus or hyperlipidemia have evidence of endothelial dysfunction, which is associated with reduced nitric oxide synthase (NOS) 3 activity (15, 16).

path(MESH:Hyperlipidemias) decreases act(a(MESH:"Nitric Oxide Synthase")) View Subject | View Object

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Evidence b1b7381650
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Endothelial dysfunction, a condition associated with reduced bioavailability of 282 vascular NO, occurs in humans and mice with hyperlipidemia (16).

path(MESH:Hyperlipidemias) increases path(HM:"Endothelial dysfunction") View Subject | View Object

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