Objective Neuregulin receptor degradation protein-1 (Nrdp1) is an E3 ubiquitin ligase that regulates the proteasomal degradation and activity of proteins involved in cell growth, inflammation and apoptosis, including ErbB3, BRUCE, MyD88 and TBK1. However, the effect of Nrdp1 on cardiac ischaemia/reperfusion (I/R) injury in vivo has not yet been investigated.
Methods and results We generated transgenic mice with cardiac-specific overexpression of Nrdp1 using α-myosin heavy chain promoter. Echocardiography demonstrated that cardiac-specific Nrdp1 expression resulted in depression of cardiac contractile function under basal condition (TG6 mice, EF, 62.74±4.40%, FS, 33.53±3.17%; WT mice, EF, 67.52±11.07%; FS, 37.64±8.64%). When subjected to 30 min of left coronary artery ischaemia and 24 h of reperfusion, the infarct size, expressed as the ratio of infarct/AAR and infarct/LV, was significantly increased in Nrdp1 TG6 mice (28.6%; 17.0%) compared with that of WT mice (18.4%; 11.4%, p<0.05). Furthermore, the survival rate after I/R in Nrdp1 TG6 mice (75.9%, 22/29) was significantly lower than that of WT mice (84.6%, 22/26). Moreover, the numbers of TUNEL-positive nuclei (22.83%; 15.78%) neutrophil and macrophage infiltration after I/R were significantly higher in Nrdp1 transgenic mice than in WT mice (p<0.05). Additionally, the activation of ErbB3, AKT, ERK1/2 and STAT3 after I/R were markedly suppressed in Nrdp1 transgenic mice compared with WT mice (p<0.01).
Conclusion These data provide the first in vivo evidence that overexpression of Nrdp1 enhances cardiac I/R injury, this effect is mediated by inhibition of ErbB3-dependent signalling pathways.