1. Academic Validation
  2. 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

  • Free Radic Biol Med. 2022 Oct 11;S0891-5849(22)00898-X. doi: 10.1016/j.freeradbiomed.2022.10.268.
Yue Yu 1 Tianyu Wu 1 Yao Lu 2 Wei Zhao 1 Jian Zhang 1 Qiushi Chen 1 Gaoyuan Ge 1 Yan Hua 1 Kaiyan Chen 1 Inam Ullah 1 Fengxiang Zhang 3
Affiliations

Affiliations

  • 1 Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
  • 2 Department of Cardiology, Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Nanjing Medical University, Xuzhou, 221009, Jiangsu, China.
  • 3 Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China. Electronic address: njzfx6@njmu.edu.cn.
Abstract

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 (25mg/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 exhibited anti-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-Exo anti-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.

Keywords

Doxorubicin; Exosomes; Ferroptosis; Glutathione peroxidase 4 (GPX4); Mechanistic target of rapamycin complex 1 (mTORC1); Mesenchymal stem cells; Thioredoxin1 (Trx1).

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