Ketoconazole induces apoptosis in rat cardiomyocytes through reactive oxygen species-mediated parkin overexpression

Area of Science:

• Cardiology
• Molecular Biology
• Pharmacology

Background:

• Azole antifungals like ketoconazole are linked to cardiac side effects, including arrhythmias.
• The precise molecular mechanism of ketoconazole's cardiotoxicity remains unclear.
• Understanding ketoconazole's effects on heart cells is crucial for patient safety.

Purpose of the Study:

• To investigate the link between ketoconazole-induced apoptosis and gene expression changes in rat cardiomyocytes.
• To elucidate the role of parkin and reactive oxygen species (ROS) in ketoconazole cardiotoxicity.

Main Methods:

• Rat cardiomyocytes were treated with varying concentrations of ketoconazole.
• Cell viability, hydrogen peroxide (H2O2) generation, and apoptosis were assessed.
• DNA microarray analysis identified differentially expressed genes, followed by validation of parkin expression and functional studies using ROS inhibitors and parkin siRNA.

Main Results:

• Ketoconazole significantly reduced cardiomyocyte viability and increased apoptosis and H2O2 generation in a dose-dependent manner.
• DNA microarray revealed significant differential expression of over 10,000 genes, with parkin being notably upregulated among apoptosis- and ROS-related genes.
• Parkin expression increased with exogenous H2O2, and ROS inhibitors or parkin knockdown attenuated ketoconazole-induced apoptosis and cell death.

Conclusions:

• Ketoconazole promotes cardiomyocyte apoptosis and reduces viability, likely through a ROS-mediated pathway.
• Ketoconazole upregulates parkin expression via ROS, contributing to cardiac cell damage.
• Targeting ROS or parkin may offer a therapeutic strategy against ketoconazole-induced cardiotoxicity.