Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway

The cancer clinical therapy of Doxorubicin (Dox) is limited by its life-threatening cardiotoxic effects. Dickkopf-1 (Dkk1), the founding member of Dkk family, is best studied and functions as an antagonist of canonical Wnt/β-catenin. Dkk1 is considered to play a broad role in a variety of biological processes, but its effects on Dox-induced cardiomyopathy is poorly understood. Here, we found that Dkk1 was significantly increased in Dox-treated groups, and this increase exacerbated Dox-induced cardiomyocyte apoptosis and mitochondrial dysfunction. Overexpressing Dkk1 aggravated Dox-induced cardiotoxicity in H9C2 cells. Similar results were detected when adding the Dkk1 active protein extracellularly. Conversely, specific antibody blocking extracellular Dkk1 attenuated Dox-cardiotoxic response. Adenovirus encoding Dkk1 was transduced through intramyocardial injection and exacerbated Dox-induced cardiomyocyte apoptosis, mitochondrial damage and heart injury in vivo. Furthermore, Wnt/β-catenin signaling was inhibited in Dox-induced cardiotoxicity, the re-activation of β-catenin relieved overexpressed Dkk1 or Dox-induced cardiotoxicity. In conclusion, these results uncovered that the crucial role of Dkk1-Wnt/β-catenin signaling axis in the process of Dox-induced cardiotoxicity and provided novel insights into the potential mechanism on cardiomyopathy caused by clinical application of Dox.