1. Academic Validation
  2. Protective role of cezanne in doxorubicin-induced cardiotoxicity by inhibiting autophagy, apoptosis and oxidative stress

Protective role of cezanne in doxorubicin-induced cardiotoxicity by inhibiting autophagy, apoptosis and oxidative stress

  • Toxicology. 2023 Jan 10;485:153426. doi: 10.1016/j.tox.2023.153426.
Jiayan Zhang 1 Yafang Zha 1 Yuheng Jiao 1 Yanyan Li 2 Song Zhang 3
Affiliations

Affiliations

  • 1 Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, China.
  • 2 Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China.
  • 3 Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, China. Electronic address: zhangsong3961@xinhuamed.com.cn.
Abstract

Doxorubicin (DOX) is frequently used in clinical practice for its broad-spectrum effects. However, its benefit is limited by a series of complications, including excessive Apoptosis and Autophagy of cardiomyocytes, overproduction of Reactive Oxygen Species (ROS) and high level of oxidative stress. As a new protein, OTU domain-containing 7B (OTUD7B), also called Cezanne, has been reported to regulate many pathological processes. However, whether it plays a role in DOX-induced cardiotoxicity is still unclear. We discovered that the Cezanne level was significantly increased in DOX-treated neonatal rat cardiomyocytes (NRCMs) and C57BL/6 J mice hearts. In vitro, the knockdown of Cezanne with adenovirus in NRCMs significantly worsened DOX-induced Apoptosis, Autophagy and oxidative stress, while Cezanne overexpression showed opposite results. In vivo, the overexpression of Cezanne using cardiomyocyte-targeted adeno-associated virus 9 (AAV9) significantly reduced cardiomyocyte Apoptosis, Autophagy and oxidative stress level when C57BL/6 J mice were subjected to DOX. Mechanistically, the overexpression of Cezanne significantly reversed the in-activation of the PI3K/Akt/mTOR pathway induced by DOX, while the inhibitors of this pathway abolished the effect of Cezanne, suggesting that the PI3K/Akt/mTOR pathway plays a role in the protective function of Cezanne. These findings indicate that Cezanne could ameliorate DOX-induced cardiotoxicity by attenuating the Apoptosis and Autophagy of cardiomyocytes and decreasing the level of oxidative stress.

Keywords

Apoptosis; Autophagy; Cardiotoxicity; Cezanne; Doxorubicin; Oxidative stress; PI3K\AKT\mTOR pathway.

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