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Human Cell

pp 1–10 | Cite as

Dexmedetomidine alleviates doxorubicin cardiotoxicity by inhibiting mitochondrial reactive oxygen species generation

  • Jie-Lu Yu
  • Yi Jin
  • Xiang-Yuan Cao
  • Hua-Hua GuEmail author
Research Article
  • 85 Downloads

Abstract

Cardiotoxicity largely limits the application of doxorubicin (Dox) for cancer treatment. Dexmedetomidine (Dex), a selective agonist of α2-adrenergic receptor, has been suggested to exert cardioprotection against myocardial injury. However, the effect and underlying mechanisms of Dex on Dox cardiotoxicity remain unknown. In this study, C57BL/6 mice were treated with Dox followed by Dex administration. Cardiomyocytes were co-incubated with Dox and Dex in vitro. The results showed that Dex markedly attenuated cardiac dysfunction induced by Dox. TUNEL staining exhibited that Dex inhibited Dox-induced cardiomyocyte apoptosis in myocardium. Moreover, the expression of anti-apoptotic protein Bcl-2 was increased, whereas the expression of pro-apoptotic protein Bax was decreased by Dex. Dox-induced the increase of reactive oxygen species (ROS), superoxide anion, and mitochondrial ROS (mROS) generation in myocardial tissues were significantly inhibited after Dex administration. In in vitro study, it was further confirmed that Dex prevented Dox-induced cardiomyocyte apoptosis and injury. However, the stimulation of mROS generation reversed the effect of Dex in cardiomyocytes. Mechanically, Dex blocked Dox-induced the ubiquitination of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), leading to the restoration of PGC-1α and downstream oxidative stress-protective molecules uncoupling protein 2 and manganese-dependent superoxide dismutase expression. Taken together, this study demonstrates that Dex exerts cardioprotection against Dox cardiotoxicity by attenuating mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis via inhibiting PGC-1α-signaling pathway inactivation. This suggests that Dex may be a potential therapeutic strategy for Dox cardiotoxicity treatment.

Keywords

Dexmedetomidine Doxorubicin Cardiotoxicity Cardiomyocyte apoptosis Oxidative stress PGC-1α 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All mice experiments were performed according to the guidelines by the Association for Assessment and Accreditation of Laboratory Animal Care International and approved by the Institutional Animal Ethics Committee of Tongji University.

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Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologyHuashan Hospital Fudan UniversityShanghaiChina
  2. 2.Department of Neurosurgery and Intensive CareShanghai Tenth People’s Hospital, Tongji University School of MedicineShanghaiChina

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