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Article: 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

TitleEfficient 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
Authors
Issue Date2016
PublisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/ijcard
Citation
International Journal of Cardiology, 2016, v. 203, p. 964-971 How to Cite?
AbstractFriedreich’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. We aimed to utilize 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. In fact, DFP was able to more significantly suppress synthesis of reactive oxygen species (ROS) than IDE at the dosages of 10 nM and 25 μM 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 DFP also modulated iron induced mitochondrial stress as reflected by mitochondria network disorganization and decline in level of respiratory chain protein. In addition, iron-response protein (IRP-1) regulatory loop was overridden by DFP as reflected by the attenuated transferrin receptor (TSFR) suppression thereby reducing further iron uptake.
Persistent Identifierhttp://hdl.handle.net/10722/214375
ISSN
2015 Impact Factor: 4.638
2015 SCImago Journal Rankings: 1.513

 

DC FieldValueLanguage
dc.contributor.authorLee, YK-
dc.contributor.authorLau, VYM-
dc.contributor.authorNg, KM-
dc.contributor.authorLai, KWH-
dc.contributor.authorHo, SL-
dc.contributor.authorTse, HF-
dc.contributor.authorSiu, DCW-
dc.contributor.authorHo, WL-
dc.date.accessioned2015-08-21T11:20:53Z-
dc.date.available2015-08-21T11:20:53Z-
dc.date.issued2016-
dc.identifier.citationInternational Journal of Cardiology, 2016, v. 203, p. 964-971-
dc.identifier.issn0167-5273-
dc.identifier.urihttp://hdl.handle.net/10722/214375-
dc.description.abstractFriedreich’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. We aimed to utilize 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. In fact, DFP was able to more significantly suppress synthesis of reactive oxygen species (ROS) than IDE at the dosages of 10 nM and 25 μM 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 DFP also modulated iron induced mitochondrial stress as reflected by mitochondria network disorganization and decline in level of respiratory chain protein. In addition, iron-response protein (IRP-1) regulatory loop was overridden by DFP as reflected by the attenuated transferrin receptor (TSFR) suppression thereby reducing further iron uptake.-
dc.languageeng-
dc.publisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/ijcard-
dc.relation.ispartofInternational Journal of Cardiology-
dc.rights© <2016>. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleEfficient 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-
dc.typeArticle-
dc.identifier.emailLee, YK: carol801@hku.hk-
dc.identifier.emailLau, VYM: vymlau@hku.hk-
dc.identifier.emailNg, KM: skykmng@hkucc.hku.hk-
dc.identifier.emailLai, KWH: kwhlai@hku.hk-
dc.identifier.emailHo, SL: slho@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.emailSiu, DCW: cwdsiu@hkucc.hku.hk-
dc.identifier.emailHo, WL: hwl2002@hku.hk-
dc.identifier.authorityNg, KM=rp01670-
dc.identifier.authorityHo, SL=rp00240-
dc.identifier.authorityTse, HF=rp00428-
dc.identifier.authoritySiu, DCW=rp00534-
dc.identifier.authorityHo, WL=rp00259-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.ijcard.2015.11.101-
dc.identifier.pmid26625322-
dc.identifier.hkuros248944-
dc.identifier.volume203-
dc.identifier.spage964-
dc.identifier.epage971-
dc.publisher.placeIreland-

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