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Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning
Life-threatening cardiomyopathy is a severe, but common, complication associated with severe trauma or sepsis. Several signaling pathways involved in apoptosis and necroptosis are linked to trauma- or sepsis-associated cardiomyopathy. However, the underling causative factors are still debatable. Hep...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869260/ https://www.ncbi.nlm.nih.gov/pubmed/29616016 http://dx.doi.org/10.3389/fimmu.2018.00393 |
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author | Zechendorf, Elisabeth Vaßen, Phillip Zhang, Jieyi Hallawa, Ahmed Martincuks, Antons Krenkel, Oliver Müller-Newen, Gerhard Schuerholz, Tobias Simon, Tim-Philipp Marx, Gernot Ascheid, Gerd Schmeink, Anke Dartmann, Guido Thiemermann, Christoph Martin, Lukas |
author_facet | Zechendorf, Elisabeth Vaßen, Phillip Zhang, Jieyi Hallawa, Ahmed Martincuks, Antons Krenkel, Oliver Müller-Newen, Gerhard Schuerholz, Tobias Simon, Tim-Philipp Marx, Gernot Ascheid, Gerd Schmeink, Anke Dartmann, Guido Thiemermann, Christoph Martin, Lukas |
author_sort | Zechendorf, Elisabeth |
collection | PubMed |
description | Life-threatening cardiomyopathy is a severe, but common, complication associated with severe trauma or sepsis. Several signaling pathways involved in apoptosis and necroptosis are linked to trauma- or sepsis-associated cardiomyopathy. However, the underling causative factors are still debatable. Heparan sulfate (HS) fragments belong to the class of danger/damage-associated molecular patterns liberated from endothelial-bound proteoglycans by heparanase during tissue injury associated with trauma or sepsis. We hypothesized that HS induces apoptosis or necroptosis in murine cardiomyocytes. By using a novel Medical-In silico approach that combines conventional cell culture experiments with machine learning algorithms, we aimed to reduce a significant part of the expensive and time-consuming cell culture experiments and data generation by using computational intelligence (refinement and replacement). Cardiomyocytes exposed to HS showed an activation of the intrinsic apoptosis signal pathway via cytochrome C and the activation of caspase 3 (both p < 0.001). Notably, the exposure of HS resulted in the induction of necroptosis by tumor necrosis factor α and receptor interaction protein 3 (p < 0.05; p < 0.01) and, hence, an increased level of necrotic cardiomyocytes. In conclusion, using this novel Medical-In silico approach, our data suggest (i) that HS induces necroptosis in cardiomyocytes by phosphorylation (activation) of receptor-interacting protein 3, (ii) that HS is a therapeutic target in trauma- or sepsis-associated cardiomyopathy, and (iii) indicate that this proof-of-concept is a first step toward simulating the extent of activated components in the pro-apoptotic pathway induced by HS with only a small data set gained from the in vitro experiments by using machine learning algorithms. |
format | Online Article Text |
id | pubmed-5869260 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-58692602018-04-03 Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning Zechendorf, Elisabeth Vaßen, Phillip Zhang, Jieyi Hallawa, Ahmed Martincuks, Antons Krenkel, Oliver Müller-Newen, Gerhard Schuerholz, Tobias Simon, Tim-Philipp Marx, Gernot Ascheid, Gerd Schmeink, Anke Dartmann, Guido Thiemermann, Christoph Martin, Lukas Front Immunol Immunology Life-threatening cardiomyopathy is a severe, but common, complication associated with severe trauma or sepsis. Several signaling pathways involved in apoptosis and necroptosis are linked to trauma- or sepsis-associated cardiomyopathy. However, the underling causative factors are still debatable. Heparan sulfate (HS) fragments belong to the class of danger/damage-associated molecular patterns liberated from endothelial-bound proteoglycans by heparanase during tissue injury associated with trauma or sepsis. We hypothesized that HS induces apoptosis or necroptosis in murine cardiomyocytes. By using a novel Medical-In silico approach that combines conventional cell culture experiments with machine learning algorithms, we aimed to reduce a significant part of the expensive and time-consuming cell culture experiments and data generation by using computational intelligence (refinement and replacement). Cardiomyocytes exposed to HS showed an activation of the intrinsic apoptosis signal pathway via cytochrome C and the activation of caspase 3 (both p < 0.001). Notably, the exposure of HS resulted in the induction of necroptosis by tumor necrosis factor α and receptor interaction protein 3 (p < 0.05; p < 0.01) and, hence, an increased level of necrotic cardiomyocytes. In conclusion, using this novel Medical-In silico approach, our data suggest (i) that HS induces necroptosis in cardiomyocytes by phosphorylation (activation) of receptor-interacting protein 3, (ii) that HS is a therapeutic target in trauma- or sepsis-associated cardiomyopathy, and (iii) indicate that this proof-of-concept is a first step toward simulating the extent of activated components in the pro-apoptotic pathway induced by HS with only a small data set gained from the in vitro experiments by using machine learning algorithms. Frontiers Media S.A. 2018-03-20 /pmc/articles/PMC5869260/ /pubmed/29616016 http://dx.doi.org/10.3389/fimmu.2018.00393 Text en Copyright © 2018 Zechendorf, Vaßen, Zhang, Hallawa, Martincuks, Krenkel, Müller-Newen, Schuerholz, Simon, Marx, Ascheid, Schmeink, Dartmann, Thiemermann and Martin. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Zechendorf, Elisabeth Vaßen, Phillip Zhang, Jieyi Hallawa, Ahmed Martincuks, Antons Krenkel, Oliver Müller-Newen, Gerhard Schuerholz, Tobias Simon, Tim-Philipp Marx, Gernot Ascheid, Gerd Schmeink, Anke Dartmann, Guido Thiemermann, Christoph Martin, Lukas Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning |
title | Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning |
title_full | Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning |
title_fullStr | Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning |
title_full_unstemmed | Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning |
title_short | Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning |
title_sort | heparan sulfate induces necroptosis in murine cardiomyocytes: a medical-in silico approach combining in vitro experiments and machine learning |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869260/ https://www.ncbi.nlm.nih.gov/pubmed/29616016 http://dx.doi.org/10.3389/fimmu.2018.00393 |
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