The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Shravanthi Mouli, Gayani Nanayakkara, Abdullah Alalasmari, Haitham Eldoumani, Xiaoyu Fu, Avery Berlin, Madhukar Lohani, Ben Nie, Robert D. Arnold, Andreas Kavazis, Forrest Smith, Ronald Beyers, Thomas Denney, Muralikrishnan Dhanasekaran, Juming Zhong, John Quindry, Rajesh Amin

Research output: Contribution to journalArticlepeer-review

Abstract

Doxorubicin (DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOXmediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. 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. Athymic mice treated with DOX (5 mg/ kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.

Original languageEnglish
Pages (from-to)H844-H859
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number5
DOIs
StatePublished - Sep 3 2015

Keywords

  • Anthracyclines
  • Cardiomyopathy
  • Frataxin
  • Iron overload
  • Mitochondrial damage
  • Oxidative stress

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