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

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.