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Article: Modeling of Friedreich ataxia-related iron overloading cardiomyopathy using patient-specific-induced pluripotent stem cells.

TitleModeling of Friedreich ataxia-related iron overloading cardiomyopathy using patient-specific-induced pluripotent stem cells.
Authors
Issue Date2013
Citation
Pflügers Archiv - European Journal of Physiology, 2013 How to Cite?
AbstractFriedreich ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is due to GAA repeat expansions within the first intron of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron–sulfur cluster biosynthesis. The triplet codon repeats lead to heterochromatin-mediated gene silencing and loss of frataxin. Nevertheless, inadequacy of existing FRDA-cardiac cellular models limited cardiomyopathy studies. We tested the hypothesis that iron homeostasis deregulation accelerates reduction in energy synthesis dynamics which contributes to impaired cardiac calcium homeostasis and contractile force. Silencing of FXN expressions occurred both in somatic FRDA-skin fibroblasts and two of the induced pluripotent stem cells (iPSC) clones; a sign of stress condition was shown in FRDA-iPSC cardiomyocytes with disorganized mitochondrial network and mitochondrial DNA (mtDNA) depletion; hypertrophic cardiac stress responses were observed by an increase in α-actinin-positive cell sizes revealed by FACS analysis as well as elevation in brain natriuretic peptide (BNP) gene expression; the intracellular iron accumulated in FRDA cardiomyocytes might be due to attenuated negative feedback response of transferring receptor (TSFR) expression and positive feedback response of ferritin (FTH1); energy synthesis dynamics, in terms of ATP production rate, was impaired in FRDA-iPSC cardiomyocytes, which were prone to iron overload condition. Energetic insufficiency determined slower Ca2+ transients by retarding calcium reuptake to sarcoplasmic reticulum (SR) and impaired the positive inotropic and chronotropic responses to adrenergic stimulation. Our data showed for the first time that FRDA-iPSCs cardiac derivatives represent promising models to study cardiac stress response due to impaired iron homeostasis condition and mitochondrial damages. The cardiomyopathy phenotype was accelerated in an iron-overloaded condition early in calcium homeostasis aspect.
Persistent Identifierhttp://hdl.handle.net/10722/193872
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLee, YKen_US
dc.contributor.authorHo, WLen_US
dc.contributor.authorSchick, Ren_US
dc.contributor.authorLau, VYMen_US
dc.contributor.authorLai, KWHen_US
dc.contributor.authorZhou, Ten_US
dc.contributor.authorLi, Yen_US
dc.contributor.authorNg, KMen_US
dc.contributor.authorHo, SLen_US
dc.contributor.authorEsteban, MAen_US
dc.contributor.authorBinah, Oen_US
dc.contributor.authorTse, HFen_US
dc.contributor.authorSiu, DCWen_US
dc.date.accessioned2014-01-28T06:30:42Z-
dc.date.available2014-01-28T06:30:42Z-
dc.date.issued2013en_US
dc.identifier.citationPflügers Archiv - European Journal of Physiology, 2013en_US
dc.identifier.urihttp://hdl.handle.net/10722/193872-
dc.description.abstractFriedreich ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is due to GAA repeat expansions within the first intron of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron–sulfur cluster biosynthesis. The triplet codon repeats lead to heterochromatin-mediated gene silencing and loss of frataxin. Nevertheless, inadequacy of existing FRDA-cardiac cellular models limited cardiomyopathy studies. We tested the hypothesis that iron homeostasis deregulation accelerates reduction in energy synthesis dynamics which contributes to impaired cardiac calcium homeostasis and contractile force. Silencing of FXN expressions occurred both in somatic FRDA-skin fibroblasts and two of the induced pluripotent stem cells (iPSC) clones; a sign of stress condition was shown in FRDA-iPSC cardiomyocytes with disorganized mitochondrial network and mitochondrial DNA (mtDNA) depletion; hypertrophic cardiac stress responses were observed by an increase in α-actinin-positive cell sizes revealed by FACS analysis as well as elevation in brain natriuretic peptide (BNP) gene expression; the intracellular iron accumulated in FRDA cardiomyocytes might be due to attenuated negative feedback response of transferring receptor (TSFR) expression and positive feedback response of ferritin (FTH1); energy synthesis dynamics, in terms of ATP production rate, was impaired in FRDA-iPSC cardiomyocytes, which were prone to iron overload condition. Energetic insufficiency determined slower Ca2+ transients by retarding calcium reuptake to sarcoplasmic reticulum (SR) and impaired the positive inotropic and chronotropic responses to adrenergic stimulation. Our data showed for the first time that FRDA-iPSCs cardiac derivatives represent promising models to study cardiac stress response due to impaired iron homeostasis condition and mitochondrial damages. The cardiomyopathy phenotype was accelerated in an iron-overloaded condition early in calcium homeostasis aspect.en_US
dc.languageengen_US
dc.relation.ispartofPflügers Archiv - European Journal of Physiologyen_US
dc.titleModeling of Friedreich ataxia-related iron overloading cardiomyopathy using patient-specific-induced pluripotent stem cells.en_US
dc.typeArticleen_US
dc.identifier.emailLee, YK: carol801@hku.hken_US
dc.identifier.emailHo, WL: hwl2002@hku.hken_US
dc.identifier.emailLau, VYM: vymlau@hku.hken_US
dc.identifier.emailLai, KWH: kwhlai@hku.hken_US
dc.identifier.emailNg, KM: h9925586@graduate.hku.hken_US
dc.identifier.emailHo, SL: slho@hku.hken_US
dc.identifier.emailTse, HF: hftse@hkucc.hku.hken_US
dc.identifier.emailSiu, DCW: cwdsiu@hkucc.hku.hken_US
dc.identifier.authorityHo, WL=rp00259en_US
dc.identifier.authorityNg, KM=rp01670en_US
dc.identifier.authorityHo, SL=rp00240en_US
dc.identifier.authorityTse, HF=rp00428en_US
dc.identifier.authoritySiu, DCW=rp00534en_US
dc.identifier.doi10.1007/s00424-013-1414-xen_US
dc.identifier.pmid24327207-
dc.identifier.hkuros227383en_US
dc.identifier.isiWOS:000340509700014-

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