Cardiotoxicity is a highly relevant, because often life-threatening, adverse effect of doxorubicin (Doxo)-based anticancer therapy. Here, we investigated the Doxo-response of cardiovascular stem/progenitor cells employing a mouse embryonic stem cell (mESC)-based in vitro differentiation model. Endothelial progenitor cells revealed a pronounced Doxo sensitivity as compared to mESC, differentiated endothelial-like (EC) and cardiomyocyte-like cells (CM) and CM progenitors, which rests on the activation of senescence. Doxo treatment of EC progenitors altered protein expression of individual endothelial markers, actin cytoskeleton morphology, mRNA expression of genes related to mitochondrial functions, autophagy, apoptosis, and DNA repair as well as mitochondrial DNA content, respiration and ATP production in the surviving differentiated EC progeny. By contrast, LDL uptake, ATP-stimulated Ca2+ release, and cytokine-stimulated ICAM-1 expression remained unaffected by the anthracycline treatment. Thus, exposure of EC progenitors to Doxo elicits isolated and persistent dysfunctions in the surviving EC progeny. In conclusion, we suggest that Doxo-induced injury of EC progenitors adds to anthracycline-induced cardiotoxicity, making this cell-type a preferential target for pharmacoprotective and regenerative strategies.

中文翻译：

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蒽环类衍生物阿霉素对mESC来源的内皮祖细胞分化功效的不同影响。

心脏毒性是高度相关的，因为基于阿霉素（Doxo）的抗癌治疗常常会危及生命，并且产生不良反应。在这里，我们调查了基于小鼠胚胎干细胞（mESC）的体外分化模型，对心血管干/祖细胞的Doxo反应。与mESC，分化的内皮样（EC）和心肌样细胞（CM）和CM祖细胞相比，内皮祖细胞显示出明显的Doxo敏感性，这取决于衰老的激活。Doxo对EC祖细胞的处理改变了单个内皮标记的蛋白质表达，肌动蛋白细胞骨架形态，与线粒体功能，自噬，凋亡和DNA修复相关的基因的mRNA表达以及线粒体DNA含量，呼吸作用和ATP的产生。相比之下，蒽环类药物治疗不会影响LDL摄取，ATP刺激的Ca2 +释放以及细胞因子刺激的ICAM-1表达。因此，将EC祖细胞暴露于Doxo会在幸存的EC子代中引起孤立和持续的功能障碍。总之，我们建议Doxo诱导的EC祖细胞损伤会增加蒽环类药物引起的心脏毒性，从而使这种细胞类型成为药物保护和再生策略的优先靶标。