Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B In Vitro
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture and Production of Cell Pellets
2.2. Microarray Data Analysis Using a Manually Generated List of Gene Symbols Related to ROS Production and Scavenging, ER Stress and HIF-1α Pathway
2.3. Immunofluorescence and Statistical Analysis
2.4. Determination of Oxidative Burst by Flow Cytometry
2.5. Immunoelectron Microscopy
2.6. Laser Scanning Confocal Microscopy
2.7. Immunoblotting
3. Results
3.1. Persistent CDV Infection of DH82cells Leads to an Increased Level of Intracellular ROS Associated with Increased Catalase and Superoxide Dismutase 2 Protein Expression
3.2. DH82Ond pi Are Characterized by an Increased HIF-1α Protein Expression Associated with an Altered Intracellular Distribution
3.3. DH82Ond pi Show an Unusual Mainly Sub-Membranous Distribution of HIF-1α
3.4. Unexpected Intracellular HIF-1α Localisation Is Associated with a Dysregulated Expression of Angiogenetic Downstream Targets
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Primary Antibody | Host Species, Clonality | Epitope Retrieval | Serum Blocking | Dilution | Secondary Antibody (1:200) | Positive Control |
---|---|---|---|---|---|---|
CDV-NP (University of Bern) | Mouse, monoclonal, clone D110 | Citrate buffer, microwave (800 W, 20´) | PBST + 3% BSA + 5% goat serum | 1:100 | GaM-Cy3 or GaM-Cy2 | n/a |
8OHdG (Abcam, Cambridge, USA) | Goat, polyclonal | Proteinase K | PBST + 3% BSA + 5% horse serum | 1:200 | DaG-Cy3 | Canine pyo-granu-lomatous endo- metritis |
SOD2 (Abcam, Cambridge, USA) | Rabbit, polyclonal | Citrate buffer, microwave (800 W, 20´) | PBST + 3% BSA + 5% goat serum | 1:200 | GaR-Cy2 | Canine brain and spinal cord |
CAT (Abcam, Cambridge, USA) | Goat, polyclonal | Citrate buffer, microwave (800 W, 20´) | PBST + 3% BSA + 5% horse serum | 1:50 | DaG-Cy3 | Canine spinal cord with fibro-carti- lagineous embolus |
HIF-1α (Novus Biologicals, Colorado, USA) | Rabbit, polyclonal | Citrate buffer, microwave (800 W, 20´) | PBST + 3% BSA + 5% goat serum | 1:500 | GaR-Cy3 or DaR-Cy2 | Canine mammary adeno- carcinoma with central necrosis |
Wheat germ agglutinin (WGA) AF633 conjugated (Invitrogen, California, USA) | none | Citrate buffer, microwave (800 W, 20´) | n/a | 1:20 | n/a | n/a |
CD63 (Sicgen, Coimbra, Portugal) | Goat, polyclonal | Citrate buffer, microwave (800 W, 20´) | PBST + 3% BSA + 5% horse serum | 1:200 | DaG-Cy3 | MDCK cell pellet |
GM-130 (BD Transduction Laboratories, North Carolina, USA) | Mouse, monoclonal, clone 35/GM130 (RUO) | Citrate buffer, microwave (800 W, 20´) | PBST + 3% BSA + 5% goat serum | 1:200 | GaM-Cy2 | n/a |
VEGF-B (My Biosource, California, USA) | Rabbit, polyclonal | Citrate buffer, microwave (800 W, 20´) | PBST + 3% BSA + 5% goat serum | 1:40 | GaR-Cy3 | Canine fetal brain, liver and kidney |
Canine Gene Symbol | Gene Name | Functional Group | Fold Change | p-Value | References |
---|---|---|---|---|---|
VEGF-B | vascular endothelial growth factor B | HIF-1a downstream | −593.197 | <0.001 | [29,39,40,41,45] |
THBS2 | thrombospondin 2 | HIF-1a downstream | −451.295 | <0.001 | [42] |
EDN1 | endothelin 1 | HIF-1a downstream | −47.795 | <0.001 | [42] |
CXCR4 | chemokine (C-X-C motif) receptor 4 | HIF-1a downstream | −13.485 | <0.001 | [39] |
SERPINE1 | serine (or cysteine) peptidase inhibitor, clade E, member 1 | HIF-1a downstream | −13.116 | <0.001 | [41,42] |
COX7B2 | cytochrome c oxidase subunit VIIb2 | ROS production; ER stress | −6.015 | <0.001 | [29,31,45] |
ITPR3 | inositol 1,4,5-triphosphate receptor, type 3 | ER stress | −4.646 | <0.001 | [37] |
THBS1 | thrombospondin 1 | HIF-1a downstream | −4.461 | <0.001 | [42] |
ERO1L | ERO1-like (S. cerevisiae) | ROS production; ER stress | −3.995 | <0.001 | [37] |
Cxcl12 | chemokine (C-X-C motif) ligand 12 | HIF-1a downstream | −3.683 | <0.001 | [39] |
NT5E | 5’-nucleotidase, ecto (CD73) | HIF-1a downstream | −3.041 | <0.001 | [39] |
CANX | calnexin | ER stress | −2.780 | <0.001 | [36] |
TXNRD3 | thioredoxin reductase 3 | ROS scavenging | −2.464 | <0.001 | [29,45] |
NDUFAF2 | NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 2 | ROS production; ER stress | −2.292 | <0.001 | [29,45] |
NDUFAB1 | NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8kDa | ROS production; ER stress | −2.261 | <0.001 | [29,45] |
DDIT3 | DNA-damage-inducible transcript 3 | ER stress | −2.087 | <0.001 | [36] |
EGLN1 | Egl nine homolog 1 (C. elegans) | HIF-1a transcription & regulation | −1.976 | 0.001 | [39,40,42,46] |
PRDX6 | peroxiredoxin 6 | ROS scavenging | −1.895 | <0.001 | [29,45] |
EGLN3 | egl nine homolog 3 (C. elegans) | HIF-1a transcription & regulation | −1.875 | 0.004 | [39,40,42,46] |
SDHD | succinate dehydrogenase complex, subunit D, integral membrane protein | ROS production; ER stress | −1.857 | <0.001 | [29,45] |
FGF2 | fibroblast growth factor 2 (basic) | HIF-1a downstream | −1.842 | 0.003 | [42] |
PDIA6 | protein disulfide isomerase family A, member 6 | ROS production; ER stress | −1.801 | <0.001 | [37] |
VHL | von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase | HIF-1a transcription & regulation | −1.771 | 0.005 | [39,40,42,45,46] |
SOD1 | superoxide dismutase 1, soluble | ROS scavenging | −1.712 | <0.001 | [29,45] |
PDIA4 | protein disulfide isomerase family A, member 4 | ROS production; ER stress | −1.678 | 0.010 | [37] |
ADM | adrenomedullin | HIF-1a downstream | −1.665 | <0.001 | [42] |
GSS | glutathione synthetase | ROS scavenging; ER stress | −1.648 | 0.001 | [37] |
NDUFC2 | NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kDa | ROS production; ER stress | −1.630 | 0.001 | [29,45] |
GCLM | glutamate-cysteine ligase, modifier subunit | ROS scavenging; ER stress | −1.565 | <0.001 | [37] |
PDIA3 | protein disulfide isomerase family A, member 3 | ROS production; ER stress | −1.533 | 0.001 | [37] |
CD274 | CD274 molecule | HIF-1a downstream | −1.515 | 0.025 | [39] |
PDGFRL | platelet-derived growth factor receptor-like | HIF-1a downstream | 1.554 | 0.004 | [39] |
UQCR11 | ubiquinol-cytochrome c reductase (6.4kD) subunit | ROS production; ER stress | 1.563 | 0.002 | [29,45] |
UQCRC2 | ubiquinol cytochrome c reductase core protein 2 | ROS production; ER stress | 1.590 | 0.021 | [29,45] |
NDUFS1 | NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75kDa (NADH-coenzyme Q reductase) | ROS production; ER stress | 1.622 | <0.001 | [29,45] |
NCF2 | neutrophil cytosolic factor 2 | ROS production | 1.639 | 0.004 | [29] |
UQCRC1 | ubiquinol-cytochrome c reductase core protein 1 | ROS production; ER stress | 1.678 | <0.001 | [29,45] |
ITPR1 | inositol 1,4,5-triphosphate receptor, type 1 | ER stress | 1.844 | 0.001 | [37] |
NDUFS7 | NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20kDa (NADH-coenzyme Q reductase) | ROS production; ER stress | 1.846 | <0.001 | [29,45] |
LONP1 | lon peptidase 1, mitochondrial | ER stress | 1.850 | 0.001 | [37] |
CCL2 | chemokine (C-C motif) ligand 2 | HIF-1a downstream | 1.866 | <0.001 | [29,42] |
HMOX1 | heme oxygenase (decycling) 1 | ROS scavenging | 1.940 | <0.001 | [29] |
NDUFA10 | NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 10, 42kDa | ROS production; ER stress | 2.009 | <0.001 | [29,45] |
PDGFA | platelet-derived growth factor alpha polypeptide | HIF-1a downstream | 2.089 | <0.001 | [39] |
PPID | peptidylprolyl isomerase D (cyclophilin D) | ER stress | 2.286 | <0.001 | [29,45] |
NDUFV3 | NADH dehydrogenase (ubiquinone) flavoprotein 3 | ROS production; ER stress | 2.362 | <0.001 | [29,45] |
ALOX5AP | arachidonate 5-lipoxygenase-activating protein | ROS production | 2.509 | <0.001 | [45] |
COX17 | COX17 homolog, cytochrome c oxidase assembly protein | ROS production; ER stress | 2.557 | 0.001 | [29,31,45] |
CAT | Catalase | ROS scavenging | 3.584 | <0.001 | [29,45] |
NQO1 | NAD(P)H dehydrogenase, quinone 1 | ROS scavenging | 3.868 | <0.001 | [29] |
XDH | xanthine dehydrogenase | ROS production; ER stress | 3.913 | 0.002 | [29,37,45] |
KITLG | KIT ligand | HIF-1a downstream | 4.174 | <0.001 | [39] |
LOC100856470 | peroxiredoxin-2-like | ROS scavenging | 5.351 | <0.001 | [29,45] |
TEK | endothelial-specific receptor tyrosine kinase | HIF-1a downstream | 5.639 | <0.001 | [39,41,42] |
PDGFC | platelet derived growth factor C | HIF-1a downstream | 6.578 | <0.001 | [39] |
TXNIP | thioredoxin interacting protein | ROS scavenging | 11.227 | 0.001 | [29] |
NCF4 | neutrophil cytosolic factor 4, 40kDa | ROS production | 67.304 | <0.001 | [29,41] |
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Armando, F.; Gambini, M.; Corradi, A.; Giudice, C.; Pfankuche, V.M.; Brogden, G.; Attig, F.; von Köckritz-Blickwede, M.; Baumgärtner, W.; Puff, C. Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B In Vitro. Viruses 2020, 12, 200. https://doi.org/10.3390/v12020200
Armando F, Gambini M, Corradi A, Giudice C, Pfankuche VM, Brogden G, Attig F, von Köckritz-Blickwede M, Baumgärtner W, Puff C. Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B In Vitro. Viruses. 2020; 12(2):200. https://doi.org/10.3390/v12020200
Chicago/Turabian StyleArmando, Federico, Matteo Gambini, Attilio Corradi, Chiara Giudice, Vanessa Maria Pfankuche, Graham Brogden, Friederike Attig, Maren von Köckritz-Blickwede, Wolfgang Baumgärtner, and Christina Puff. 2020. "Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B In Vitro" Viruses 12, no. 2: 200. https://doi.org/10.3390/v12020200