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Background  Cardiac cell death and generation of oxidative stress contribute to doxorubicin (DOX)-induced cardiac dysfunction. E3 ligase  Nrdp1  plays a critical role in the regulation of cell apoptosis, inflammation and production of reactive oxygen species (ROS), which may contribute to heart failure. However, the role of  Nrdp1  in DOX-induced cardiac injury remains to be determined.    Methods and Results  We examined the effect of  Nrdp1  overexpression with DOX treatment in rat neonatal cardiomyocytes and mouse heart tissue. Cardiomyocytes were infected with adenovirus containing GFP (Ad-GFP),  Nrdp1  wild-type (Ad- Nrdp1 ) or the dominant-negative form of  Nrdp1  (Ad-Dn- Nrdp1 ), then treated with DOX for 24 hr. DOX treatment increased cell death and apoptosis, with Ad- Nrdp1  infection enhancing these actions but Ad-Dn- Nrdp1  infection attenuating these effects. Furthermore, 5 days after a single injection of DOX (20 mg/kg, intraperitoneally),  Nrdp1  transgenic mice (TG) showed decreased cardiac function and increased apoptosis, autophagy and oxidative stress as compared with wild-type (WT) mice ( P <0.01). Survival rate was significantly lower in  Nrdp1  TG mice than in WT mice 10 days after DOX injection ( P <0.01).    Conclusions/Significance  These results were associated with decreased activation of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) signaling pathways.  Nrdp1  may be a key mediator in the development of cardiac dysfunction after DOX treatment and associated with inhibition of Akt, ERK1/2 and STAT3.  Nrdp1  may be a new therapeutic target in protecting against the cardiotoxic effects of DOX.

Overexpression of Nrdp1 in the Heart Exacerbates Doxorubicin-Induced Cardiac Dysfunction in Mice