Exosomal thioredoxin-1 from hypoxic human umbilical cord mesenchymal stem cells inhibits ferroptosis in doxorubicin-induced cardiotoxicity via mTORC1 signaling
Exosomal thioredoxin-1 from hypoxic human umbilical cord mesenchymal stem cells inhibits ferroptosis in doxorubicin-induced cardiotoxicity via mTORC1 signaling
复制标题
来自缺氧人脐带间充质干细胞的外泌体硫氧还蛋白-1通过mTORC1信号传导抑制多柔比星诱导的心脏毒性中的铁死亡
DOI：
10.1016/j.freeradbiomed.2022.10.268
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发表时间：
2022
影响因子：
7.4
通讯作者：
Fengxiang Zhang
中科院分区：
文献类型：
--
作者：
Yue Yu;Tianyu Wu;Yao Lu;Wei Zhao;Jian Zhang;Qiushi Chen;Gaoyuan Ge;Yan Hua;Kaiyan Chen;Inam Ullah;Fengxiang Zhang
阿霉素（DOX）是一种临床常用的化疗药物，其心脏毒性常使其病理过程中出现铁凋亡。人脐带间充质干细胞（HucMSC）衍生的外泌体（HucMSCs-Exo）已被证明可有效治疗心血管疾病。本研究旨在比较常氧HucMSCs-Exo（Exo）和缺氧HucMSCs-Exo（Hypo-Exo）对阿霉素诱导的铁凋亡的治疗作用，并探讨其机制。采用两次腹腔注射DOX（共25 mg/kg）的方法成功建立了急性心脏毒性模型。通过超离心提取Exo和Hypo-Exo并进行表征。与Exo相比，Hypo-Exo和Ferrostatin-1（Fer-1）具有上级的抑制阿霉素诱导的铁凋亡作用，表现为降低丙二醛（MDA）和铁含量，提高谷胱甘肽（GSH）水平以及铁凋亡相关基因的表达，包括谷胱甘肽过氧化物酶4（GPX 4）和谷胱甘肽内过氧化物酶2（Ptgs 2）的mRNA水平。基于定量蛋白质组学分析，我们发现硫氧还蛋白1（Trx 1）在新生大鼠心肌细胞（NRCMs）中的表达显著上调，并通过激活雷帕霉素复合物1（mTORC 1）的机制靶点而表现出抗铁凋亡活性。Trx 1敲除和雷帕霉素（mTORC 1抑制剂）部分消除了Hypo-Exo的保护作用。此外，我们的数据表明溶质载体家族7成员11（SLC 7A 11）是GPX 4蛋白合成的关键。总之，Hypo-Exo在DOX诱导的心脏毒性中表现出更好的铁凋亡抑制作用。Trx 1介导的mTORC 1激活对于低外抗铁凋亡过程至关重要，该过程涉及GPX 4蛋白合成增加和铁过载减少。本研究表明，Hypo-Exo可能是一种潜在的策略，以防止铁细胞凋亡的阿霉素诱导的心脏毒性。
Doxorubicin (DOX), a clinical chemotherapeutic drug, is often annoyed by its cardiotoxicity which involves ferroptosis in its pathological progress. Human umbilical cord mesenchymal stem cells (HucMSCs)-derived exosomes (HucMSCs-Exo) are proven effective in treating cardiovascular diseases. This study aimed to compare the therapeutic effects between normoxic HucMSCs-Exo (Exo) and hypoxic HucMSCs-Exo (Hypo-Exo) on DOX-induced ferroptosis and explore the underlying mechanisms. An acute cardiotoxicity model was successfully constructed by administrating two doses intraperitoneal injections of DOX (25 mg/kg in total). Exo and Hypo-Exo were extracted by ultracentrifugation and characterized. Compared with Exo, Hypo-Exo and Ferrostatin-1 (Fer-1) exerted superior effects on inhibiting DOX-induced ferroptosis, as evidenced by decreasing malondialdehyde (MDA), iron content and increasing glutathione (GSH) level as well as ferroptosis-related genes expression including prostaglandin-endoperoxide synthase 2 (Ptgs2) mRNA level and glutathione peroxidase 4 (GPX4) protein level. Based on quantitative proteomics analysis, we found that thioredoxin1 (Trx1) was remarkably upregulated in Hypo-Exo and exhibitedanti-ferroptosis activity via activating the mechanistic target of rapamycin complex 1 (mTORC1) in neonatal rat cardiomyocytes (NRCMs). Trx1 knockdown and rapamycin (an mTORC1 inhibitor) partially abolished the protective effects of Hypo-Exo. Furthermore, our data indicated that solute carrier family 7 member 11 (SLC7A11) was critical for GPX4 protein synthesis. In conclusion, Hypo-Exo exhibited a better suppression of ferroptosis in DOX-induced cardiotoxicity. Trx1-mediated mTORC1 activation is critical for the Hypo-Exoanti-ferroptosis process, which involves increased GPX4 protein synthesis and decreased iron overload. This study indicated that Hypo-Exo may present a potential strategy against ferroptosis in DOX-induced cardiotoxicity.