Research Paper Volume 13, Issue 23 pp 25256—25270

MicroRNA therapy confers anti-senescent effects on doxorubicin-related cardiotoxicity by intracellular and paracrine signaling

Wenzheng Xia1,2, *, , Bowen Chang3, *, , Liqun Li2, , Tingting Hu4, , Jiaqi Ye4, , Hanbin Chen4, , Wenfeng Li4, , Tao Zan1, *, , Meng Hou4, *,&, ,

  • 1 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
  • 2 Department of Plastic Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
  • 3 Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
  • 4 Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
* Equal contribution

Received: April 11, 2021       Accepted: November 22, 2021       Published: December 5, 2021
How to Cite

Copyright: © 2021 Xia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Doxorubicin (Dox), an important anthracycline, is a potent anticancer agent that is used for treating solid tumors and hematologic malignancies. However, its clinical use is hampered by cardiac cardiotoxicity. This study aimed to investigate the cardioprotective potential of miR-199a-3p. Continuous Dox treatment not only markedly induced cardiomyocyte senescence but also resulted in a growing number of senescence-associated secretory phenotype (SASP) cardiomyocytes, frequently leading to heart senescence. This study showed that miR-199a-3p was downregulated in cardiomyocytes when exposed to Dox. The cardiac-specific overexpression of miR-199a-3p promoted cell cycle re-entry and cell proliferation, resulting in relief from cardiac senescence. Also, the elevation of miR-199a-3p inhibited the generation of SASP, thus, hampering the spread of senescence. In cardiomyocytes, the modulation of miR-199a-3p changed the levels of senescence-related protein GATA4. The ectopic expression of GATA4 blunted the anti-senescence effect of miR-199a-3p. Together, the data supported a role for miR-199a-3p during Dox cardiotoxicity. The elevation of miR-199a-3p might provide a dual therapeutic advantage in Dox cardiotoxicity therapy by simultaneously preventing cardiac senescence and reducing the spread of senescence.


Dox: Doxorubicin; SASP: senescence-associated secretory phenotype; miR: microRNA; qRT-PCR: quantitative reverse transcription–polymerase chain reaction; SA-β-gal assay: senescence-associated β-galactosidase assay; 3’-UTRs: 3′-untranslated regions; ROS: reactive oxygen species; DMEM: Dulbecco’s modified Eagle’s medium; PI: propidium iodide; CCK-8: cell counting kit-8; MMPs: matrix metalloproteinases; DAPI: 4′,6-Diamidine-2′-phenylindole dihydrochloride; DiI: 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; SD: standard deviation; ANOVA: repeated-measures analysis of variance.