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

Area of Science:

• Cardiology
• Oncology
• Molecular Biology

Background:

• Doxorubicin (Dox) is a vital chemotherapy agent, but its use is limited by severe cardiotoxicity.
• Dickkopf-1 (Dkk1) antagonizes Wnt/β-catenin signaling, a pathway implicated in various biological processes.
• The role of Dkk1 in Dox-induced cardiomyopathy remains largely unexplored.

Purpose of the Study:

• To investigate the role of Dickkopf-1 (Dkk1) in doxorubicin (Dox)-induced cardiotoxicity.
• To elucidate the underlying molecular mechanisms involving the Wnt/β-catenin signaling pathway.

Main Methods:

• Assessed Dkk1 levels in Dox-treated cells and animal models.
• Utilized cell culture (H9C2 cells) to overexpress Dkk1 or block it with antibodies.
• Employed adenovirus-mediated gene delivery for in vivo Dkk1 overexpression via intramyocardial injection.
• Examined cardiomyocyte apoptosis, mitochondrial function, and Wnt/β-catenin signaling activity.

Main Results:

• Dkk1 levels were significantly elevated in Dox-treated groups, correlating with increased cardiomyocyte apoptosis and mitochondrial dysfunction.
• Overexpression of Dkk1 aggravated Dox-induced cardiotoxicity in vitro and in vivo.
• Blocking extracellular Dkk1 attenuated Dox-induced cardiotoxic effects.
• Doxorubicin treatment inhibited Wnt/β-catenin signaling, and its reactivation mitigated Dkk1-mediated cardiotoxicity.

Conclusions:

• The Dkk1-Wnt/β-catenin signaling axis plays a critical role in mediating Dox-induced cardiotoxicity.
• Targeting Dkk1 or reactivating Wnt/β-catenin signaling may offer novel therapeutic strategies to prevent Dox-induced cardiomyopathy.