Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
Cells. 2019 Oct 9;8(10):1224. doi: 10.3390/cells8101224.
Doxorubicin (Dox) is an effective antineoplastic agent used to treat cancers, but its use is limited as Dox induces adverse cardiotoxic effects. Dox-induced cardiotoxicity (DIC) can lead to heart failure and death. There is no study that investigates whether embryonic stem cell-derived exosomes (ES-Exos) in DIC can attenuate inflammation-induced pyroptosis, pro-inflammatory M1 macrophages, inflammatory cell signaling, and adverse cardiac remodeling. For this purpose, we transplanted ES-Exos and compared with ES-cells (ESCs) to examine pyroptosis, inflammation, cell signaling, adverse cardiac remodeling, and their influence on DIC induced cardiac dysfunction. Therefore, we used C57BL/6J mice ages 10 ± 2 weeks and divided them into four groups ( = 6-8/group): Control, Dox, Dox + ESCs, and Dox + ES-Exos. Our data shows that the Dox treatment significantly increased expression of inflammasome markers (TLR4 and NLRP3), pyroptotic markers (caspase-1, IL1-β, and IL-18), cell signaling proteins (MyD88, p-P38, and p-JNK), pro-inflammatory M1 macrophages, and TNF-α cytokine. This increased pyroptosis, inflammation, and cell signaling proteins were inhibited with ES-Exos or ESCs. Moreover, ES-Exos or ESCs increased M2 macrophages and anti-inflammatory cytokine, IL-10. Additionally, ES-Exos or ESCs treatment inhibited significantly cytoplasmic vacuolization, myofibril loss, hypertrophy, and improved heart function. In conclusion, for the first time we demonstrated that Dox-induced pyroptosis and cardiac remodeling are ameliorated by ES-Exos or ESCs.
多柔比星（Dox）是一种有效的抗肿瘤药物，用于治疗癌症，但由于其诱导心脏毒性作用，其应用受到限制。多柔比星诱导的心脏毒性（DIC）可导致心力衰竭和死亡。目前尚无研究探讨 DIC 中胚胎干细胞衍生的外泌体（ES-Exos）是否能减轻炎症诱导的细胞焦亡、促炎 M1 型巨噬细胞、炎症细胞信号和不良心脏重构。为此，我们移植了 ES-Exos，并与 ES 细胞（ESCs）进行了比较，以研究细胞焦亡、炎症、细胞信号、不良心脏重构及其对 DIC 诱导的心脏功能障碍的影响。因此，我们使用 10 ± 2 周龄的 C57BL/6J 小鼠，将其分为四组（每组 6-8 只）：对照组、多柔比星组、多柔比星+ESCs 组和多柔比星+ES-Exos 组。我们的数据显示，多柔比星处理显著增加了炎症小体标志物（TLR4 和 NLRP3）、细胞焦亡标志物（caspase-1、IL1-β 和 IL-18）、细胞信号蛋白（MyD88、p-P38 和 p-JNK）、促炎 M1 型巨噬细胞和 TNF-α 细胞因子的表达。ES-Exos 或 ESCs 抑制了这种细胞焦亡、炎症和细胞信号蛋白的增加。此外，ES-Exos 或 ESCs 增加了 M2 型巨噬细胞和抗炎细胞因子 IL-10。此外，ES-Exos 或 ESCs 治疗显著抑制了细胞质空泡化、肌原纤维丢失、肥大，并改善了心脏功能。总之，我们首次证明 DIC 诱导的细胞焦亡和心脏重构可通过 ES-Exos 或 ESCs 得到改善。
