File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Modeling of lamin A/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells

TitleModeling of lamin A/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells
Authors
KeywordsDilated cardiomyopathy
Induced pluripotent stem cells
LMNA
Issue Date2012
PublisherImpact Journals LLC. The Journal's web site is located at http://www.impactaging.com
Citation
Aging, 2012, v. 4 n. 11, p. 803-822 How to Cite?
AbstractAIMS: We identified an autosomal dominant non-sense mutation (R225X) in exon 4 of the lamin A/C (LMNA) gene in a Chinese family spanning 3 generations with familial dilated cardiomyopathy (DCM). In present study, we aim to generate induced pluripotent stem cells derived cardiomyocytes (iPSC-CMs) from an affected patient with R225X and another patient bearing LMNA frame-shift mutation for drug screening. METHODS and RESULTS: Higher prevalence of nuclear bleb formation and micronucleation was present in LMNA(R225X/WT) and LMNA(Framshift/WT) iPSC-CMs. Under field electrical stimulation, percentage of LMNA-mutated iPSC-CMs exhibiting nuclear senescence and cellular apoptosis markedly increased. shRNA knockdown of LMNA replicated those phenotypes of the mutated LMNA field electrical stress. Pharmacological blockade of ERK1/2 pathway with MEK1/2 inhibitors, U0126 and selumetinib (AZD6244) significantly attenuated the pro-apoptotic effects of field electric stimulation on the mutated LMNA iPSC-CMs. CONCLUSION: LMNA-related DCM was modeled in-vitro using patient-specific iPSC-CMs. Our results demonstrated that haploinsufficiency due to R225X LMNA non-sense mutation was associated with accelerated nuclear senescence and apoptosis of iPSC- CMs under electrical stimulation, which can be significantly attenuated by therapeutic blockade of stress-related ERK1/2 pathway.
Persistent Identifierhttp://hdl.handle.net/10722/152741
ISSN
2017 Impact Factor: 5.179
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSiu, CW-
dc.contributor.authorLee, YK-
dc.contributor.authorHo, JCY-
dc.contributor.authorLai, WH-
dc.contributor.authorChan, YC-
dc.contributor.authorNg, KM-
dc.contributor.authorWong, LY-
dc.contributor.authorAu, KW-
dc.contributor.authorLau, YM-
dc.contributor.authorZhang, J-
dc.contributor.authorLay, KW-
dc.contributor.authorColman, A-
dc.contributor.authorTse, HF-
dc.date.accessioned2012-07-16T09:47:28Z-
dc.date.available2012-07-16T09:47:28Z-
dc.date.issued2012-
dc.identifier.citationAging, 2012, v. 4 n. 11, p. 803-822-
dc.identifier.issn1945-4589-
dc.identifier.urihttp://hdl.handle.net/10722/152741-
dc.description.abstractAIMS: We identified an autosomal dominant non-sense mutation (R225X) in exon 4 of the lamin A/C (LMNA) gene in a Chinese family spanning 3 generations with familial dilated cardiomyopathy (DCM). In present study, we aim to generate induced pluripotent stem cells derived cardiomyocytes (iPSC-CMs) from an affected patient with R225X and another patient bearing LMNA frame-shift mutation for drug screening. METHODS and RESULTS: Higher prevalence of nuclear bleb formation and micronucleation was present in LMNA(R225X/WT) and LMNA(Framshift/WT) iPSC-CMs. Under field electrical stimulation, percentage of LMNA-mutated iPSC-CMs exhibiting nuclear senescence and cellular apoptosis markedly increased. shRNA knockdown of LMNA replicated those phenotypes of the mutated LMNA field electrical stress. Pharmacological blockade of ERK1/2 pathway with MEK1/2 inhibitors, U0126 and selumetinib (AZD6244) significantly attenuated the pro-apoptotic effects of field electric stimulation on the mutated LMNA iPSC-CMs. CONCLUSION: LMNA-related DCM was modeled in-vitro using patient-specific iPSC-CMs. Our results demonstrated that haploinsufficiency due to R225X LMNA non-sense mutation was associated with accelerated nuclear senescence and apoptosis of iPSC- CMs under electrical stimulation, which can be significantly attenuated by therapeutic blockade of stress-related ERK1/2 pathway.-
dc.languageeng-
dc.publisherImpact Journals LLC. The Journal's web site is located at http://www.impactaging.com-
dc.relation.ispartofAging-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectDilated cardiomyopathy-
dc.subjectInduced pluripotent stem cells-
dc.subjectLMNA-
dc.titleModeling of lamin A/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells-
dc.typeArticle-
dc.identifier.emailSiu, CW: cwdsiu@hkucc.hku.hk-
dc.identifier.emailLee, YK: carol801@hku.hk-
dc.identifier.emailHo, JCY: jennyho@hku.hk-
dc.identifier.emailLai, WH: kwhlai@hku.hk-
dc.identifier.emailChan, YC: yauchi@graduate.hku.hk-
dc.identifier.emailNg, KM: h9925586@graduate.hku.hk-
dc.identifier.emailWong, LY: navywong@hkucc.hku.hk-
dc.identifier.emailAu, KW: aukawing@hkucc.hku.hk-
dc.identifier.emailLau, YM: vymlau@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.authoritySiu, CW=rp00534-
dc.identifier.authorityLee, YK=rp02636-
dc.identifier.authorityChan, YC=rp01502-
dc.identifier.authorityNg, KM=rp01670-
dc.identifier.authorityTse, HF=rp00428-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.18632/aging.100503-
dc.identifier.pmid23362510-
dc.identifier.pmcidPMC3560431-
dc.identifier.scopuseid_2-s2.0-84872506168-
dc.identifier.hkuros201069-
dc.identifier.volume4-
dc.identifier.issue11-
dc.identifier.spage803-
dc.identifier.epage822-
dc.identifier.isiWOS:000312289900011-
dc.publisher.placeUnited States-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats