2. Academic Validation
  3. 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.
PMID: 36241072 DOI: 10.1016/j.freeradbiomed.2022.10.268
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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