Identification of the molecular basis of doxorubicin-induced cardiotoxicity

Area of Science:

• Cardiovascular biology
• Molecular toxicology
• Cancer therapeutics

Background:

• Doxorubicin is a widely used chemotherapy agent.
• Doxorubicin-induced cardiotoxicity is a significant clinical concern.
• The precise mechanisms underlying doxorubicin cardiotoxicity are not fully elucidated.

Purpose of the Study:

• To investigate the role of topoisomerase-IIβ (Top2b) in doxorubicin-induced cardiotoxicity.
• To determine if cardiomyocyte-specific deletion of Top2b confers protection against doxorubicin.
• To explore the molecular pathways involved in doxorubicin cardiotoxicity mediated by Top2b.

Main Methods:

• Generation of cardiomyocyte-specific Top2b knockout mice.
• Administration of doxorubicin to wild-type and knockout mice.
• Assessment of cardiac function, DNA damage, mitochondrial biogenesis, and gene expression.
• Analysis of reactive oxygen species (ROS) generation.

Main Results:

• Cardiomyocyte-specific deletion of Top2b prevented doxorubicin-induced DNA double-strand breaks.
• Deletion of Top2b normalized transcriptome changes related to mitochondrial dysfunction.
• Top2b deletion protected cardiomyocytes from ROS formation and preserved mitochondrial biogenesis.
• Mice lacking Top2b in cardiomyocytes were protected from doxorubicin-induced progressive heart failure.

Conclusions:

• Doxorubicin-induced cardiotoxicity is critically dependent on topoisomerase-IIβ activity within cardiomyocytes.
• Targeting Top2b in cardiomyocytes offers a potential strategy to mitigate doxorubicin-related heart damage.
• This study identifies Top2b as a key mediator of doxorubicin's detrimental effects on the heart.