Efficient attenuation of Friedreich's ataxia (FRDA) cardiomyopathy by modulation of iron homeostasis-human induced pluripotent stem cell (hiPSC) as a drug screening platform for FRDA

Int J Cardiol. 2016 Jan 15:203:964-71. doi: 10.1016/j.ijcard.2015.11.101. Epub 2015 Nov 17.

Abstract

Background: Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is caused by silencing of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron-sulfur cluster biosynthesis.

Methods: Application of our previously established FRDA human induced pluripotent stem cell (hiPSC) derived cardiomyocytes model as a platform to assess the efficacy of treatment with either the antioxidant coenzyme Q10 analog, idebenone (IDE) or the iron chelator, deferiprone (DFP), which are both under clinical trial.

Results: DFP was able to more significantly suppress synthesis of reactive oxygen species (ROS) than IDE at the dosages of 25 μM and 10nM respectively which agreed with the reduced rate of intracellular accumulation of iron by DFP treatment from 25 to 50 μM. With regard to cardiac electrical-contraction (EC) coupling function, decay velocity of calcium handling kinetics in FRDA-hiPSC-cardiomyocytes was significantly improved by DFP treatment but not by IDE. Further mechanistic studies revealed that DFP also modulated iron induced mitochondrial stress as reflected by mitochondria network disorganization and decline level of respiratory chain protein, succinate dehydrogenase (CxII) and cytochrome c oxidase (COXIV). In addition, iron-response protein (IRP-1) regulatory loop was overridden by DFP as reflected by resumed level of ferritin (FTH) back to basal level and the attenuated transferrin receptor (TSFR) mRNA level suppression thereby reducing further iron uptake.

Conclusions: DFP modulated iron homeostasis in FRDA-hiPSC-cardiomyocytes and effectively relieved stress-stimulation related to cardiomyopathy. The resuming of redox condition led to the significantly improved cardiac prime events, cardiac electrical-coupling during contraction.

Keywords: Cardiomyopathy; Deferiprone; Friedreich's ataxia; Idebenone; Induced pluripotent stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Deferiprone
  • Drug Evaluation, Preclinical / methods*
  • Frataxin
  • Friedreich Ataxia / genetics
  • Friedreich Ataxia / metabolism
  • Friedreich Ataxia / therapy*
  • Gene Expression Regulation
  • Homeostasis
  • Humans
  • Induced Pluripotent Stem Cells*
  • Iron / metabolism*
  • Iron Chelating Agents / pharmacology
  • Iron-Binding Proteins / biosynthesis
  • Iron-Binding Proteins / genetics
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Oxidative Stress
  • Pyridones / pharmacology*
  • RNA / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquinone / analogs & derivatives*
  • Ubiquinone / pharmacology

Substances

  • Antioxidants
  • Iron Chelating Agents
  • Iron-Binding Proteins
  • Pyridones
  • Ubiquinone
  • Deferiprone
  • RNA
  • Iron
  • idebenone