The irreversible loss of cardiomyocytes due to oxidative stress is the main cause of heart dysfunction following ischemia/reperfusion (I/R) injury and ageing-induced cardiomyopathy. Here, we report that CUEDC2, a CUE domain-containing protein, plays a critical role in oxidative stress-induced cardiac injury. Cuedc2(-/-) cardiomyocytes exhibited a greater resistance to oxidative stress-induced cell death. Loss of CUEDC2 enhanced the antioxidant capacity of cardiomyocytes, promoted reactive oxygen species (ROS) scavenging, and subsequently inhibited the redox-dependent activation of signaling pathways. Notably, CUEDC2 promoted E3 ubiquitin ligases tripartite motif-containing 33 (TRIM33)-mediated the antioxidant enzyme, glutathione peroxidase 1 (GPX1) ubiquitination, and proteasome-dependent degradation. Ablation of CUEDC2 upregulated the protein level of GPX1 in the heart significantly. Strikingly, in vivo, the infarct size of Cuedc2(-/-) heart was significantly decreased after I/R injury, and aged Cuedc2(-/-) mice preserved better heart function as the overall ROS levels in their hearts were significantly lower. Our results demonstrated a novel role of CUEDC2 in cardiomyocyte death regulation. Manipulating CUEDC2 level might be an attractive therapeutic strategy for promoting cardiomyocyte survival following oxidative stress-induced cardiac injury.
© 2016 The Authors. Published under the terms of the CC BY 4.0 license.
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CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability.
In EMBO Molecular Medicine on 1 July 2016 by Jian, Z., Liang, B., et al.
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Biochemistry and Molecular biology
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In Cell Reports on 26 June 2014 by Chen, Y., Wang, S. X., et al.
CUEDC2, a CUE-domain-containing protein, modulates inflammation, but its involvement in tumorigenesis is still poorly understood. Here, we report that CUEDC2 is a key regulator of macrophage function and critical for protection against colitis-associated tumorigenesis. CUEDC2 expression is dramatically upregulated during macrophage differentiation, and CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is modulated by miR- 324-5p. We find that Cuedc2 KO mice are more susceptible to dextran-sodium-sulfate-induced colitis, and macrophage transplantation results suggest that the increased susceptibility results from the dysfunction of macrophages lacking CUEDC2. Furthermore, we find that Cuedc2 KO mice are more prone to colitis-associated cancer. Importantly, CUEDC2 expression is almost undetectable in macrophages in human colon cancer, and this decreased CUEDC2 expression is associated with high levels of interleukin-4 and miR-324-5p. Thus, CUEDC2 plays a crucial role in modulating macrophage function and is associated with both colitis and colon tumorigenesis.Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.1.A
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WB
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Mus musculus (House mouse)
CUEDC2 degradation was induced by ischemia/reperfusion in cardiac tissueCUEDC2 protein levels in mouse tissues. Adult (12‐week‐old) mouse was sacrificed and the total protein was extracted from the liver, kidney, lung, spleen, heart, stomach, intestine, prostate, testis, brain, and thymus.(top) I...
more
CUEDC2 degradation was induced by ischemia/reperfusion in cardiac tissueCUEDC2 protein levels in mouse tissues. Adult (12‐week‐old) mouse was sacrificed and the total protein was extracted from the liver, kidney, lung, spleen, heart, stomach, intestine, prostate, testis, brain, and thymus.(top) In vivo cardiac ischemia/reperfusion model protocol (30‐minute ischemia followed by indicated times of reperfusion). (bottom) Mice were subjected to reversible ischemia in vivo for 30 min and reperfused for different time periods. Protein was extracted from the area at risk of heart at the indicated time points and subjected to immunoblot analysis of CUEDC2 and CUEDC1. Representative results were shown from 2 mice at each time point, and experiments were repeated for three times.Isolated primary rat neonatal cardiomyocytes were subjected to hypoxia with serum‐free medium for 6 h and reoxygenated accompanying adding serum back for different time period in vitro and the protein level of CUEDC2 was tested at different time points during reoxygenation. Each experiment was repeated for three times.CUEDC2 protein level was plotted using the immunohistochemical scores as described in methods. (left) Plot of CUEDC2 scores in each BZ and DZ (n = 9 patients). (right) Representative images from immunohistochemical staining for CUEDC2 in the tissues from patients who suffered acute myocardial infarctions. The boxed areas in the left images are magnified in the middle and right images. DZ, distant zone; BZ, border zone. Scale bars, 250 μm (left), 50 μm (middle and right). *P = 0.001. Data were shown as mean ± SEM and analyzed by paired t‐test.Source data are available online for this figure.
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.8.A
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Mus musculus (House mouse)
Rescuing CUEDC2 expression eliminated the protective effects in Cuedc2−/− miceImmunoblotting for CUEDC2 protein level. Four weeks after tail vein injection of rAAV9‐CUEDC2, indicated mice tissues were harvested and subjected to immunoblotting to detect CUEDC2 protein level. Ctl: heart of rAAV9‐GF...
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Rescuing CUEDC2 expression eliminated the protective effects in Cuedc2−/− miceImmunoblotting for CUEDC2 protein level. Four weeks after tail vein injection of rAAV9‐CUEDC2, indicated mice tissues were harvested and subjected to immunoblotting to detect CUEDC2 protein level. Ctl: heart of rAAV9‐GFP injected mice.Animals were injected by rAAV9‐CUEDC2 in a different amount of viral genomes (VG). Heart tissues were then analyzed by immunoblotting to detect CUEDC2 transduction. Tubulin protein level was examined for normalization purposes.The ratios of AAR to LV, IRI to AAR, and IRI to LV are shown. n = 10 mice in WT + rAAV‐GFP group and Cuedc2−/− + rAAV‐GFP group; n = 12 mice in Cuedc2−/− + rAAV‐CUEDC2 (1 × 1010 VG) group and Cuedc2−/− + rAAV‐CUEDC2 (1 × 1011 VG) group. *P = 0.0055, **P = 0.0146, ***P = 0.0200, ****P = 0.0377.Effect of rAAV9‐CUEDC2 treatment on echocardiography indices of left ventricle function recovery post‐I/R measured by fractional shortening (FS) and ejection fraction (EF). WT+ rAAV‐GFP (n = 10); Cuedc2−/− + rAAV‐GFP (n = 10); Cuedc2−/− + rAAV‐CUEDC2 (Low dose) (n = 12); Cuedc2−/− + rAAV‐CUEDC2 (High dose) (n = 12). **P < 0.0001.Data information: Data were shown as mean ± SEM and analyzed by two‐way ANOVA followed by Bonferroni's multiple comparison test.Source data are available online for this figure.
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.8.B
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WB
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Mus musculus (House mouse)
Rescuing CUEDC2 expression eliminated the protective effects in Cuedc2−/− miceImmunoblotting for CUEDC2 protein level. Four weeks after tail vein injection of rAAV9‐CUEDC2, indicated mice tissues were harvested and subjected to immunoblotting to detect CUEDC2 protein level. Ctl: heart of rAAV9‐GF...
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Rescuing CUEDC2 expression eliminated the protective effects in Cuedc2−/− miceImmunoblotting for CUEDC2 protein level. Four weeks after tail vein injection of rAAV9‐CUEDC2, indicated mice tissues were harvested and subjected to immunoblotting to detect CUEDC2 protein level. Ctl: heart of rAAV9‐GFP injected mice.Animals were injected by rAAV9‐CUEDC2 in a different amount of viral genomes (VG). Heart tissues were then analyzed by immunoblotting to detect CUEDC2 transduction. Tubulin protein level was examined for normalization purposes.The ratios of AAR to LV, IRI to AAR, and IRI to LV are shown. n = 10 mice in WT + rAAV‐GFP group and Cuedc2−/− + rAAV‐GFP group; n = 12 mice in Cuedc2−/− + rAAV‐CUEDC2 (1 × 1010 VG) group and Cuedc2−/− + rAAV‐CUEDC2 (1 × 1011 VG) group. *P = 0.0055, **P = 0.0146, ***P = 0.0200, ****P = 0.0377.Effect of rAAV9‐CUEDC2 treatment on echocardiography indices of left ventricle function recovery post‐I/R measured by fractional shortening (FS) and ejection fraction (EF). WT+ rAAV‐GFP (n = 10); Cuedc2−/− + rAAV‐GFP (n = 10); Cuedc2−/− + rAAV‐CUEDC2 (Low dose) (n = 12); Cuedc2−/− + rAAV‐CUEDC2 (High dose) (n = 12). **P < 0.0001.Data information: Data were shown as mean ± SEM and analyzed by two‐way ANOVA followed by Bonferroni's multiple comparison test.Source data are available online for this figure.
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.5.A
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Mus musculus (House mouse)
CUEDC2 destabilizes GPX1 by facilitating its ubiquitin‐proteasome‐dependent degradationLysates from MEF‐WT or MEF‐Cuedc2−/− cells treated with 20 μM cycloheximide (CHX) for the indicated times were subjected to immunoblotting (left). Relative GPX1 levels were quantified by densitometry (right).ME...
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CUEDC2 destabilizes GPX1 by facilitating its ubiquitin‐proteasome‐dependent degradationLysates from MEF‐WT or MEF‐Cuedc2−/− cells treated with 20 μM cycloheximide (CHX) for the indicated times were subjected to immunoblotting (left). Relative GPX1 levels were quantified by densitometry (right).MEF‐Cuedc2−/− cells were transfected with increasing amounts of FLAG‐CUEDC2 (mouse) plasmids (1 μg and 2 μg). At 24 h after transfection, the cells were treated with the proteasome inhibitor MG‐132 (10 μM). The cells were cultured for additional 6 h and subjected to immunoblotting.HEK293T cells were transfected with the FLAG‐GPX1, HA‐CUEDC2, and Myc‐ubiquitin plasmids as indicated and treated with MG‐132 (10 μM) for 6 h before harvest. Cell lysates were immunoprecipitated (IP) with anti‐FLAG (M2). The immunoprecipitates were analyzed by Western blot using an anti‐GPX1 antibody. Whole‐cell lysates (WCL) were analyzed by Western blots with anti‐FLAG or anti‐HA antibody to determine the protein of Flag‐GPX1 and HA‐CUEDC2.The heart tissue lysates from wild‐type and Cuedc2−/− mice were incubated with IgG or anti‐GPX1 antibody and then captured on protein G–Sepharose beads. The immunoprecipitates were analyzed by immunoblotting with an anti‐ubiquitin antibody.HEK293T cells were transfected with the Flag‐CUEDC2 or Flag‐CUEDC2▵CUE (deletion of the CUE domain of CUEDC2) and treated with MG‐132 (10 μM) for 6 h before harvest. Cell lysates were immunoprecipitated (IP) with anti‐Flag (M2). The immunoprecipitates were analyzed by Western blot using an anti‐GPX1 antibody. Whole‐cell lysates (WCL) were analyzed by Western blots with anti‐Flag or anti‐GPX1 antibody to determine the protein of Flag‐CUEDC2 and GPX1. v: vector.Source data are available online for this figure.
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.3.A
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Mus musculus (House mouse)
Loss of CUEDC2 inhibits ROS and redox‐dependent pathways induced by oxidative stressProtein was extracted from the area at risk of left ventricle from wild‐type or Cuedc2−/− mice with 30‐minute ischemia followed by 30‐minute reperfusion and subjected to immunoblot analysis. Representative results...
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Loss of CUEDC2 inhibits ROS and redox‐dependent pathways induced by oxidative stressProtein was extracted from the area at risk of left ventricle from wild‐type or Cuedc2−/− mice with 30‐minute ischemia followed by 30‐minute reperfusion and subjected to immunoblot analysis. Representative results from 2 mice are shown, and each experiment was repeated for three times.Neonatal mouse cardiomyocytes were subjected to hypoxia for 6 h, followed by the indicated times of reoxygenation, before the protein was extracted and subjected to immunoblot analysis.Luciferase assay of WT or Cuedc2−/− MEFs transiently transfected with an NF‐κB‐responsive luciferase reporter and then, 1 d later, treated for 6 h with TNF (10 ng ml−1; TNF) or for H/R. * P = 0.0032, n = 3 per group, **P = 0.013, n = 3 per group.Wild‐type and Cuedc2−/− mice were treated with a sham or I/R operation in vivo. Three hours after the onset of reperfusion, the mRNA levels of tumor necrosis factor α (TNF‐α), interleukin 6 (IL‐6), and interleukin 23 (IL‐23) were tested. *P = 0.0005, **P = 0.0001, n = 3 per group.Data information: Data were shown as mean ± SEM and analyzed by unpaired t‐test.Source data are available online for this figure.
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.3.B
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WB
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Mus musculus (House mouse)
Loss of CUEDC2 inhibits ROS and redox‐dependent pathways induced by oxidative stressProtein was extracted from the area at risk of left ventricle from wild‐type or Cuedc2−/− mice with 30‐minute ischemia followed by 30‐minute reperfusion and subjected to immunoblot analysis. Representative results...
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Loss of CUEDC2 inhibits ROS and redox‐dependent pathways induced by oxidative stressProtein was extracted from the area at risk of left ventricle from wild‐type or Cuedc2−/− mice with 30‐minute ischemia followed by 30‐minute reperfusion and subjected to immunoblot analysis. Representative results from 2 mice are shown, and each experiment was repeated for three times.Neonatal mouse cardiomyocytes were subjected to hypoxia for 6 h, followed by the indicated times of reoxygenation, before the protein was extracted and subjected to immunoblot analysis.Luciferase assay of WT or Cuedc2−/− MEFs transiently transfected with an NF‐κB‐responsive luciferase reporter and then, 1 d later, treated for 6 h with TNF (10 ng ml−1; TNF) or for H/R. * P = 0.0032, n = 3 per group, **P = 0.013, n = 3 per group.Wild‐type and Cuedc2−/− mice were treated with a sham or I/R operation in vivo. Three hours after the onset of reperfusion, the mRNA levels of tumor necrosis factor α (TNF‐α), interleukin 6 (IL‐6), and interleukin 23 (IL‐23) were tested. *P = 0.0005, **P = 0.0001, n = 3 per group.Data information: Data were shown as mean ± SEM and analyzed by unpaired t‐test.Source data are available online for this figure.
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.6.D
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Mus musculus (House mouse)
CUEDC2 facilitated E3 ligase TRIM33‐mediated GPX1 degradationHEK293T cells were transfected with increasing amounts of Flag‐TRIM33 expression vectors, and 48 h after transfection, cell lysates were subjected to immunoblotting (IB) using antibodies as indicated.HEK293T cells were transfected with ...
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CUEDC2 facilitated E3 ligase TRIM33‐mediated GPX1 degradationHEK293T cells were transfected with increasing amounts of Flag‐TRIM33 expression vectors, and 48 h after transfection, cell lysates were subjected to immunoblotting (IB) using antibodies as indicated.HEK293T cells were transfected with increasing amounts of Flag‐FBXW7 expression vectors, and 48 h after transfection, cell lysates were subjected to immunoblotting (IB).HEK293T cells were transfected as indicated; at 18 h after transfection, the cells were treated with the proteasome inhibitor MG132(20 μM) for 6 h and then harvested. Cell lysates were immunoprecipitated by Flag antibody (M2 beads) and ubiquitin‐conjugated GPX1 was detected by Western blotting with anti‐Myc antibody.HEK293T cells were transfected with either control or CUEDC2 siRNA and with increasing amounts of Flag‐TRIM33 expression vectors; cell lysates were subjected to immunoblotting (IB) using antibodies as indicated.Source data are available online for this figure.
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.4.E
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WB
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Mus musculus (House mouse)
CUEDC2 deletion promotes the antioxidant potential of cardiomyocytes by upregulating GPX1 levelsProtein was extracted from the left ventricle of wild‐type or Cuedc2−/− adult mice (12 weeks old) and subjected to immunoblot analysis (3 mice per group).Wild‐type or Cuedc2−/− mice were subjected to a...
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CUEDC2 deletion promotes the antioxidant potential of cardiomyocytes by upregulating GPX1 levelsProtein was extracted from the left ventricle of wild‐type or Cuedc2−/− adult mice (12 weeks old) and subjected to immunoblot analysis (3 mice per group).Wild‐type or Cuedc2−/− mice were subjected to a heart ischemia for 30 minutes in vivo, followed by reperfusion for the indicated times. Protein was extracted from the area at risk of left ventricle and subjected to immunoblot analysis.GPX1 protein level was plotted using the immunohistochemical scores as described in methods. (left) Representative images from immunohistochemical staining for GPX1 in tissues from patients who suffered acute myocardial infarctions. (right) Plot of GPX1 scores in each BZ and DZ (n = 9 patients). DZ, distant area; BZ, border zone. Scale bars, 250 μm (left). *P = 0.0039.Primary neonatal mouse cardiomyocytes expressing control or GPX1 shRNA by adenovirus infection were treated with H2O2 (1 mM) for 3 h. Cell viability was detected by FACS. *P = 0.0001; **P = 0.0275, n = 3 wells per group. NS, not significant.Primary neonatal mouse cardiomyocytes were transfected with adenovirus carrying control or GPX1 shRNA, and the efficiency of GPX1 knockdown was tested by immunoblotting.Primary neonatal mouse cardiomyocytes expressing control or GPX1 shRNA by adenovirus infection were subjected to H2O2 (1 mM) for 30 minutes and then stained with 5 μM CellROX® Deep Red Reagent and analyzed by flow cytometry. *P = 0.0056; **P = 0.0218, n = 3 wells per group. NS, not significant.Data information: Data were shown as mean ± SEM and analyzed by paired t‐test (C) or by two‐way ANOVA followed by Bonferroni's multiple comparison test (D and F). Source data are available online for this figure.
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.1.C
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WB
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Mus musculus (House mouse)
CUEDC2 degradation was induced by ischemia/reperfusion in cardiac tissueCUEDC2 protein levels in mouse tissues. Adult (12‐week‐old) mouse was sacrificed and the total protein was extracted from the liver, kidney, lung, spleen, heart, stomach, intestine, prostate, testis, brain, and thymus.(top) I...
more
CUEDC2 degradation was induced by ischemia/reperfusion in cardiac tissueCUEDC2 protein levels in mouse tissues. Adult (12‐week‐old) mouse was sacrificed and the total protein was extracted from the liver, kidney, lung, spleen, heart, stomach, intestine, prostate, testis, brain, and thymus.(top) In vivo cardiac ischemia/reperfusion model protocol (30‐minute ischemia followed by indicated times of reperfusion). (bottom) Mice were subjected to reversible ischemia in vivo for 30 min and reperfused for different time periods. Protein was extracted from the area at risk of heart at the indicated time points and subjected to immunoblot analysis of CUEDC2 and CUEDC1. Representative results were shown from 2 mice at each time point, and experiments were repeated for three times.Isolated primary rat neonatal cardiomyocytes were subjected to hypoxia with serum‐free medium for 6 h and reoxygenated accompanying adding serum back for different time period in vitro and the protein level of CUEDC2 was tested at different time points during reoxygenation. Each experiment was repeated for three times.CUEDC2 protein level was plotted using the immunohistochemical scores as described in methods. (left) Plot of CUEDC2 scores in each BZ and DZ (n = 9 patients). (right) Representative images from immunohistochemical staining for CUEDC2 in the tissues from patients who suffered acute myocardial infarctions. The boxed areas in the left images are magnified in the middle and right images. DZ, distant zone; BZ, border zone. Scale bars, 250 μm (left), 50 μm (middle and right). *P = 0.001. Data were shown as mean ± SEM and analyzed by paired t‐test.Source data are available online for this figure.
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Collected and cropped from EMBO Molecular Medicine by CiteAb, provided under a CC-BY license
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.1.B
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WB
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Mus musculus (House mouse)
CUEDC2 degradation was induced by ischemia/reperfusion in cardiac tissueCUEDC2 protein levels in mouse tissues. Adult (12‐week‐old) mouse was sacrificed and the total protein was extracted from the liver, kidney, lung, spleen, heart, stomach, intestine, prostate, testis, brain, and thymus.(top) I...
more
CUEDC2 degradation was induced by ischemia/reperfusion in cardiac tissueCUEDC2 protein levels in mouse tissues. Adult (12‐week‐old) mouse was sacrificed and the total protein was extracted from the liver, kidney, lung, spleen, heart, stomach, intestine, prostate, testis, brain, and thymus.(top) In vivo cardiac ischemia/reperfusion model protocol (30‐minute ischemia followed by indicated times of reperfusion). (bottom) Mice were subjected to reversible ischemia in vivo for 30 min and reperfused for different time periods. Protein was extracted from the area at risk of heart at the indicated time points and subjected to immunoblot analysis of CUEDC2 and CUEDC1. Representative results were shown from 2 mice at each time point, and experiments were repeated for three times.Isolated primary rat neonatal cardiomyocytes were subjected to hypoxia with serum‐free medium for 6 h and reoxygenated accompanying adding serum back for different time period in vitro and the protein level of CUEDC2 was tested at different time points during reoxygenation. Each experiment was repeated for three times.CUEDC2 protein level was plotted using the immunohistochemical scores as described in methods. (left) Plot of CUEDC2 scores in each BZ and DZ (n = 9 patients). (right) Representative images from immunohistochemical staining for CUEDC2 in the tissues from patients who suffered acute myocardial infarctions. The boxed areas in the left images are magnified in the middle and right images. DZ, distant zone; BZ, border zone. Scale bars, 250 μm (left), 50 μm (middle and right). *P = 0.001. Data were shown as mean ± SEM and analyzed by paired t‐test.Source data are available online for this figure.
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Collected and cropped from EMBO Molecular Medicine by CiteAb, provided under a CC-BY license
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In EMBO Mol Med on 1 July 2016 by Jian, Z., Liang, B., et al.
Fig.4.B
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WB
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Mus musculus (House mouse)
CUEDC2 deletion promotes the antioxidant potential of cardiomyocytes by upregulating GPX1 levelsProtein was extracted from the left ventricle of wild‐type or Cuedc2−/− adult mice (12 weeks old) and subjected to immunoblot analysis (3 mice per group).Wild‐type or Cuedc2−/− mice were subjected to a...
more
CUEDC2 deletion promotes the antioxidant potential of cardiomyocytes by upregulating GPX1 levelsProtein was extracted from the left ventricle of wild‐type or Cuedc2−/− adult mice (12 weeks old) and subjected to immunoblot analysis (3 mice per group).Wild‐type or Cuedc2−/− mice were subjected to a heart ischemia for 30 minutes in vivo, followed by reperfusion for the indicated times. Protein was extracted from the area at risk of left ventricle and subjected to immunoblot analysis.GPX1 protein level was plotted using the immunohistochemical scores as described in methods. (left) Representative images from immunohistochemical staining for GPX1 in tissues from patients who suffered acute myocardial infarctions. (right) Plot of GPX1 scores in each BZ and DZ (n = 9 patients). DZ, distant area; BZ, border zone. Scale bars, 250 μm (left). *P = 0.0039.Primary neonatal mouse cardiomyocytes expressing control or GPX1 shRNA by adenovirus infection were treated with H2O2 (1 mM) for 3 h. Cell viability was detected by FACS. *P = 0.0001; **P = 0.0275, n = 3 wells per group. NS, not significant.Primary neonatal mouse cardiomyocytes were transfected with adenovirus carrying control or GPX1 shRNA, and the efficiency of GPX1 knockdown was tested by immunoblotting.Primary neonatal mouse cardiomyocytes expressing control or GPX1 shRNA by adenovirus infection were subjected to H2O2 (1 mM) for 30 minutes and then stained with 5 μM CellROX® Deep Red Reagent and analyzed by flow cytometry. *P = 0.0056; **P = 0.0218, n = 3 wells per group. NS, not significant.Data information: Data were shown as mean ± SEM and analyzed by paired t‐test (C) or by two‐way ANOVA followed by Bonferroni's multiple comparison test (D and F). Source data are available online for this figure.
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Collected and cropped from EMBO Molecular Medicine by CiteAb, provided under a CC-BY license
Image 1 of 11