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PubMed: 28400318

Title
Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress.
Journal
Free radical biology & medicine
Volume
108
Issue
None
Pages
452-464
Date
2017-07-01
Authors
Vinchi F | Ingoglia G | Petrillo S | Tolosano E | Altruda F | Cimino J | De Franceschi L | Ghigo A | Hirsch E | Kreitmeier K | Maier LS | Rex N | Sag CM | Silengo L | Wagner S

Evidence 2552a14cf6
JSON

As expected, α-tocopherol treatment prevented ROS accumulation and the induction of anti-oxidant genes in the heart (Figure 6A, B and see Figure 8 in [37]).

a(CHEBI:"alpha-tocopherol") decreases a(MESH:"Reactive Oxygen Species") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence 4a6c2e153a
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Consistently, we measured increased lipid peroxidation in both cells and tissues exposed to free heme, which can be rescued by α-tocopherol, an agent able to react with lipid radicals and interrupt the oxidation reaction.

a(CHEBI:"alpha-tocopherol") decreases bp(MESH:"Lipid Peroxidation") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Discussion

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

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence c633e00eae
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Heme promotes endothelial dysfunction by inducing the expression of adhesion molecules and reducing nitric oxide (NO) availability, which causes vasoconstriction [9-14].

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

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Cell Ontology (CL)
endothelial cell
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Introduction

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

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Cell Ontology (CL)
endothelial cell
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a(CHEBI:heme) decreases a(CHEBI:"nitric oxide") View Subject | View Object

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Cell Ontology (CL)
endothelial cell
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bp(GO:vasoconstriction) negativeCorrelation a(CHEBI:"nitric oxide") View Subject | View Object

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Cell Ontology (CL)
endothelial cell
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Evidence 6a862391eb
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As well as NAC, Hx co-treatment significantly improved systolic Ca2+ transients and accelerated Ca2+ transient decay kinetics, which resulted in a significant improvement of cardiomyocyte contractility (Figure 4A-E).

a(CHEBI:acetylcysteine) negativeCorrelation path(HP:"Impaired myocardial contractility") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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p(MGI:Hpx) negativeCorrelation path(HP:"Impaired myocardial contractility") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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path(HP:"Impaired myocardial contractility") negativeCorrelation p(MGI:Hpx) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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path(HP:"Impaired myocardial contractility") negativeCorrelation a(CHEBI:acetylcysteine) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence 450903f5e9
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Moreover, heme-derived ROS induce the proliferation of smooth muscle cells, that participate in vasculopathy associated with atherosclerosis and hypertension [15].

a(CHEBI:heme) increases a(MESH:"Reactive Oxygen Species") View Subject | View Object

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endothelial cell
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a(MESH:"Reactive Oxygen Species") increases bp(MESH:"Cell Proliferation") View Subject | View Object

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Cell Ontology (CL)
smooth muscle cell
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a(MESH:"Reactive Oxygen Species") positiveCorrelation path(MESH:Atherosclerosis) View Subject | View Object

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Cell Ontology (CL)
smooth muscle cell
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a(MESH:"Reactive Oxygen Species") positiveCorrelation path(MESH:Hypertension) View Subject | View Object

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smooth muscle cell
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path(MESH:Atherosclerosis) positiveCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

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smooth muscle cell
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path(MESH:Hypertension) positiveCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

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smooth muscle cell
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Evidence 579f51c4d8
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In agreement with data on pro-oxidant effects of heme in neonatal mouse CMs (Figure 1D-F), oxidative stress was significantly increased in adult rat CMs exposed to free heme (see Figure 1 in [37]).

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

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence 5e0a188dc4
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Consistently, the mRNA levels of Glutathione reductase (Gsr), -Glutamylcysteine synthetase (-Gcs) and thioredoxin reductase (Thiored red), anti-oxidant systems important in resistance of cardiac cell to oxidative damage [40, 41], were increased to a higher extent in CMs treated with either albumin heme or heme alone, compared to cells treated with Hx-heme (Figure 1F and see Figure 3 in [37]).

a(CHEBI:heme) increases r(MGI:Gsr) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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a(CHEBI:heme) increases r(MGI:Gclc) View Subject | View Object

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regular cardiac myocyte
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a(CHEBI:heme) increases complex(r(MGI:Txnrd1), r(MGI:Txnrd2), r(MGI:Txnrd3)) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Results

p(MGI:Hpx) decreases r(MGI:Gsr) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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p(MGI:Hpx) decreases r(MGI:Gclc) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
Text Location
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p(MGI:Hpx) decreases complex(r(MGI:Txnrd1), r(MGI:Txnrd2), r(MGI:Txnrd3)) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence 393cde8bd6
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These data collectively indicate that heart free heme accumulating when Hx is lost is responsible for systolic dysfunction.

a(CHEBI:heme) positiveCorrelation path(HP:"Left ventricular systolic dysfunction") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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path(HP:"Left ventricular systolic dysfunction") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence 8882c0f19b
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Excess production of reactive oxygen species (ROS) has been implicated in progression of chronic heart failure as well as in other cardiovascular disorders including ischemia-reperfusion injury and cardiovascular complications of hemolytic diseases [2-7].

a(MESH:"Reactive Oxygen Species") positiveCorrelation path(MESH:"Heart Failure") View Subject | View Object

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a(MESH:"Reactive Oxygen Species") positiveCorrelation path(MESH:"Reperfusion Injury") View Subject | View Object

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path(MESH:"Heart Failure") positiveCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

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path(MESH:"Reperfusion Injury") positiveCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

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Evidence 1f9f8552f7
JSON

Mechanistically, heme-derived ROS may directly modify Ca2+ handling proteins (such as the RyR2 or SERCA2a) [35, 57], and may also activate intracellular stress kinases, such as CaMKII [58], which in turn phosphorylate the same Ca2+ effectors and ultimately exacerbate Ca2+ mishandling.

a(MESH:"Reactive Oxygen Species") positiveCorrelation act(p(PFAM:"CaMKII_AD")) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Discussion

bp(HM:"Calcium Homeostasis") negativeCorrelation act(p(PFAM:"CaMKII_AD")) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Discussion

act(p(PFAM:"CaMKII_AD")) positiveCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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act(p(PFAM:"CaMKII_AD")) negativeCorrelation bp(HM:"Calcium Homeostasis") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Discussion

Evidence 0a797f53b4
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Hx-heme-treated CMs were protected from heme accumulation, compared to cells treated with albumin-heme or heme alone (Figure 1A), indicating that Hx prevents heme entry in cardiac cells.

p(MGI:Hpx) decreases a(CHEBI:heme) View Subject | View Object

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regular cardiac myocyte
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Evidence a5273b36f8
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Being heme a well-known pro-oxidant agent [17], we then evaluated ROS levels in CMs exposed to heme alone or bound to either Hx or albumin. In the presence of Hx-heme complexes, CMs were protected from ROS formation, if compared to CMs treated with either albumin-heme complexes or heme alone (Figure 1D).

p(MGI:Hpx) decreases a(MESH:"Reactive Oxygen Species") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence 260a0728fc
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Consistently, HO-1 mRNA and protein levels were higher in hearts from Hx-/- mice than in controls (Figure 2B). Immunohistochemistry for HO-1 on heart sections indicated higher HO-1 expression in cardiomyocytes from Hx-/- mice than in wild-type animals (Figure 2B).

p(MGI:Hpx) decreases p(MGI:Hmox1) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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p(MGI:Hpx) decreases r(MGI:Hmox1) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence d243a7e8bd
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Moreover, in CMs the heme-mediated induction of the iron exporter Ferroportin (Fpn) was abrogated by Hx treatment while the down-regulation of the iron importer Transferrin receptor 1 (TfR1) was significantly reduced by Hx (see Figure 3 in [37]) further indicating that Hx limits heme-iron accumulation within the cell.

p(MGI:Hpx) decreases p(MGI:Slc40a1) View Subject | View Object

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regular cardiac myocyte
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p(MGI:Hpx) increases p(MGI:Tfrc) View Subject | View Object

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regular cardiac myocyte
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Evidence fa52e0b878
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Moreover, the mRNA levels of Fpn and Flvcr1a were increased in Hx-/- mice, whereas those of the iron importers Divalent Metal Transporter 1 (Dmt1) and Tfr1 were decreased (see Figure 4 in [37]).

p(MGI:Hpx) increases p(MGI:Tfrc) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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p(MGI:Hpx) decreases r(MGI:Slc40a1) View Subject | View Object

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regular cardiac myocyte
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p(MGI:Hpx) decreases r(MGI:Flvcr1) View Subject | View Object

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regular cardiac myocyte
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p(MGI:Hpx) increases p(MGI:Slc11a2) View Subject | View Object

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regular cardiac myocyte
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Evidence 0300ad7998
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Consistently, Hx treatment blunted heme-mediated induction of the heme exporter Feline Leukemia Virus subgroup C Receptor 1(Flvcr1) [31, 38, 39] in H9c2 cells (see Figure 3 in [37]).

p(MGI:Hpx) negativeCorrelation p(MGI:Flvcr1) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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p(MGI:Flvcr1) negativeCorrelation p(MGI:Hpx) View Subject | View Object

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regular cardiac myocyte
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Evidence 52d6216bb0
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Staining of CMs with a fluorescent probe for specific detection of mitochondrial superoxide (Mito-sox) confirmed lower oxidative stress in cells exposed to Hx-heme than in those exposed to albumin-heme or heme alone (Figure 1E).

p(MGI:Hpx) decreases bp(MESH:"Oxidative Stress") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence 8dd3599914
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Both ROS and lipid peroxidation were increased in the heart of Hx-/- mice compared to that of wild-type animals (Figure 2C, D).

p(MGI:Hpx) decreases bp(MESH:"Oxidative Stress") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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p(MGI:Hpx) decreases bp(MESH:"Lipid Peroxidation") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence 01f5e48370
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The data were reproduced in H9c2 cells in which we were also able to demonstrate that Hx limits protein nitrosylation, another hallmark of cellular oxidative damage (see Figure 2 in [37]).

p(MGI:Hpx) decreases bp(GO:"protein nitrosylation") View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence be596ad734
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Consistently, the oxidative stress responsive gene Gsr was up-regulated in the heart of Hx-/- mice compared to wild-type animals (Figure 2E).

p(MGI:Hpx) decreases g(MGI:Gsr) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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Evidence c9699eaec7
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Cardiac contractility was severely impaired in 3 month-old Hx-/- mice compared to wild-type controls, as evidenced by significantly lower fractional shortening (FS) and ejection fraction (EF) (Figure 3A-C).

p(MGI:Hpx) negativeCorrelation path(HP:"Impaired myocardial contractility") View Subject | View Object

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regular cardiac myocyte
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path(HP:"Impaired myocardial contractility") negativeCorrelation p(MGI:Hpx) View Subject | View Object

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regular cardiac myocyte
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Evidence 92839ee6cf
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Consistently, CaMKII-dependent phosphorylation of RyR2 (Ser-2814) and Phospholamban (PLB) (Thr-17) were significantly higher in Hx-/- hearts than in wild-type controls (Figure 5C, D).

p(MGI:Hpx) decreases p(MGI:Ryr2, pmod(Ph, Ser, 2814)) View Subject | View Object

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regular cardiac myocyte
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p(MGI:Hpx) decreases p(MGI:Pln, pmod(Ph, Thr, 17)) View Subject | View Object

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Cell Ontology (CL)
regular cardiac myocyte
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