Cumulative DOX dosing (25mg/kg) 5 treatments 5mg/kg per dose results in cardiac hypertrophy in mice.
DOX reduces FXN expression in mice treated with cumulative dosing 25 mg/kg (5mg/kg/ per dose). Further DOX reduces FXN total and active version of FXN in H9C2 cardiomyoblasts.
DOX induces increased free iron accumulation into the mitochondria. Novel RNP1 sensing probe measures free iron mitochondrial iron accumulation via a FRET based assay.
Doxorubicin (DOX) is a highly effective anti-neoplastic agent; however its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Recent studies have attributed the cause for the cardiotoxicity to DOX mediated mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. Our current published findings report that frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, has a significant role in development of DOX mediated mitochondrial dysfunction and culminates to heart failure.
DOX (5mg/kg, 1 dose per week for 5 weeks, followed by 2 weeks recovery) treated athymic mice displayed compensatory cardiac repair mechanisms including increased left ventricular hypertrophy and progressing towards functional decompensation as observed by impaired cardiac hemodynamic performance parameters, measured by MRI. Further in this process, we observed significant reduction in FXN expression in DOX-treated animals and cardiomyocyte cell lines resulting in increased mitochondrial iron accumulation and the ensuing ROS formation.
This observation was paralleled in DOX treated cardiomyocytes by a significant reduction in the mitochondrial bioenergetics as observed by the reduction in OXPHOS. Surprisingly, similar results were observed in our frataxin knock down cardiomyocytes. In order to further understand the role of FXN we constructed frataxin over expressing cardiomyocytes (FXN-OE) which displayed inherent cardioprotection against DOX mediated mitochondrial iron accumulation, ROS formation and reduction of mitochondrial bioenergetics. Lastly our FXN-OE cardiomyocytes were protected from cardiac hypertrophy as induced by DOX and thus could serve as a therapeutic adjuvant to prevent DOX cardiotoxicity.
Currently we have developed a FXN-OE mouse model to better understand the role of FXN in DOX mediated cardiac hypertrophy.