Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical- In silico Approach Combining In vitro Experiments and Machine Learning

• Published in: Frontiers in immunology Vol. 9; p. 393
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 20.03.2018
• Subjects: apoptosis; Immunology; modeling; necroptosis; optimization; Petri nets; septic cardiomyopathy; small data; modeling; Petri nets; optimization; septic cardiomyopathy; apoptosis; necroptosis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2018.00393

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- 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 cytochrome C and the activation of caspase 3 (both  < 0.001). Notably, the exposure of HS resulted in the induction of necroptosis by tumor necrosis factor α and receptor interaction protein 3 (  < 0.05;  < 0.01) and, hence, an increased level of necrotic cardiomyocytes. In conclusion, using this novel Medical- 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 experiments by using machine learning algorithms.