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

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.

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