Analysis of tyrosine kinase inhibitor-mediated decline in contractile force in rat engineered heart tissue

Fabian Jacob, Amina Y. Yonis, Friederike Cuello, Pradeep Luther, Thomas Schulze, Alexandra Eder, Thomas Streichert, Ingra Mannhardt, Marc N. Hirt, Sebastian Schaaf, Justus Stenzig, Thomas Force, Thomas Eschenhagen, Arne Hansen

    22 Citations (Scopus)


    Introduction: Left ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an on-target or off-target mechanism. Methods and Results: We studied concentration-response curves and time courses for nine TKIs in three-dimensional, force generating engineered heart tissue (EHT) from neonatal rat heart cells. We detected a concentration- and time-dependent decline in contractile force for gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib and lestaurtinib and no decline in contractile force for erlotinib and dasatinib after 96 hours of incubation. The decline in contractile force was associated with an impairment of autophagy (LC3 Western blot) and appearance of autophagolysosomes (transmission electron microscopy). Conclusion: This study demonstrates the feasibility to study TKI-mediated force effects in EHTs and identifies an association between a decline in contractility and inhibition of autophagic flux.

    Original languageEnglish
    Article numbere0145937
    JournalPLoS ONE
    Issue number2
    Publication statusPublished - 01.02.2016

    Research Areas and Centers

    • Academic Focus: Biomedical Engineering


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