Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue.
Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue.
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DOI：
10.1371/journal.pone.0145937
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hansen A
中科院分区：
文献类型：
--
作者：
Jacob F;Yonis AY;Cuello F;Luther P;Schulze T;Eder A;Streichert T;Mannhardt I;Hirt MN;Schaaf S;Stenzig J;Force T;Eschenhagen T;Hansen A
左心功能不全是许多酪氨酸激酶抑制剂(TKI)常见且可能严重的副作用。毒性的模式尚未确定，但可能包括线粒体或肌瘤功能受损、自噬或血管生成，无论是靶点上的机制还是靶外机制。我们研究了九种TKI在新生大鼠心肌细胞的三维力生工程心脏组织(EHT)中的浓度-反应曲线和时间过程。经96小时孵育后，吉非替尼、拉帕替尼、舒尼替尼、伊马替尼、索拉非尼、凡得坦尼和雷洛替尼的收缩力均呈浓度和时间依赖性下降，而厄洛替尼和达沙替尼的收缩力无下降。收缩力的下降与自噬功能受损(LC 3 Western印迹)和自噬溶酶体的出现(透射电子显微镜)有关。这项研究证明了在EHTS中研究TKI介导力效应的可行性，并确定了收缩能力下降和自噬通量抑制之间的联系。
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. 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). 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.