The Role of Frataxin in Doxorubicin Mediated Cardiac Hypertrophy

Abstract

Doxorubicin (DOX) is a highly effective anti-neoplastic agent, used to treat a wide range of cancer. However, the clinical application of DOX is limited due to its dose dependent cardiotoxic complications which eventually lead to heart failure. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX mediated mitochondrial dysfunction and ensuing cardiac hypertrophy. In order to accomplish this, we treated our athymic mice with DOX (5mg/kg, 1 dose per week with 5 treatments, followed by 2 weeks recovery) and observed left ventricular hypertrophy. Further following DOX administration, we also observed significant reduction in FXN expression in vivo and in H9C2 cardiomyoblast cell lines which resulted in increased mitochondrial iron accumulation and ROS formation. To better understand the cardioprotective role of FXN against DOX, we constructed frataxin over expressing cardiomyoblasts (FXN-OE) which displayed cardioprotection against DOX mediated mitochondrial iron accumulation, reactive oxygen species (ROS) and reduced mitochondrial bioenergetics. Our next objective was to better understand the mechanism by which DOX reduces FXN expression. We observed an increase in ubiquitination of FXN by DOX which may possibly lead to its degradation. Our results collectively suggest a possible post translational alteration including elevated ubiquitination and hyperacetylation of FXN with DOX.

Lastly we have determined a potential pharmacological mechanism to improve FXN expression and thus offer cardioprotection against DOX mediated cardiac damage. We have for the first time demonstrated that pharmacological activation of peroxisome proliferator activated receptor δ (PPARδ) by a high affinity PPARδ agonist GW0742 was cardioprotective against DOX mediated cardiotoxicity by increasing FXN expression levels. In this manner, we observed improvement in mitochondrial energy parameters including reduced ROS production and glutathione status in response to PPARδ activation in DOX treated H9C2 cardiomyoblasts. Lastly, PPARδ mediated increase in FXN conferred significant protection against DOX mediated cardiac hypertrophy thereby suggesting that PPARδ mediated improvement in FXN was cardioprotective against DOX mediated cardiac damage. Together our findings reveal novel insights into the development of DOX mediated cardiomyopathy novel mitochondrial targets to mitigate its cardiotoxicity.