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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

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  • Medientyp: E-Artikel
  • Titel: Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning
  • Beteiligte: 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
  • Erschienen: Frontiers Media SA, 2018
  • Erschienen in: Frontiers in Immunology
  • Sprache: Nicht zu entscheiden
  • DOI: 10.3389/fimmu.2018.00393
  • ISSN: 1664-3224
  • Schlagwörter: Immunology ; Immunology and Allergy
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>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-<jats:italic>In silico</jats:italic> 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 <jats:italic>via</jats:italic> cytochrome C and the activation of caspase 3 (both <jats:italic>p</jats:italic> &amp;lt; 0.001). Notably, the exposure of HS resulted in the induction of necroptosis by tumor necrosis factor α and receptor interaction protein 3 (<jats:italic>p</jats:italic> &amp;lt; 0.05; <jats:italic>p</jats:italic> &amp;lt; 0.01) and, hence, an increased level of necrotic cardiomyocytes. In conclusion, using this novel Medical-<jats:italic>In silico</jats:italic> 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 <jats:italic>in vitro</jats:italic> experiments by using machine learning algorithms.</jats:p>
  • Zugangsstatus: Freier Zugang