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Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations

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dc.contributor.authorRivera-Torres, Jose
dc.contributor.authorCalvo, Conrado J.
dc.contributor.authorLlach, Anna
dc.contributor.authorGuzman-Martinez, Gabriela
dc.contributor.authorCaballero, Ricardo
dc.contributor.authorGonzalez-Gomez, Cristina
dc.contributor.authorJimenez-Borreguero, Luis J.
dc.contributor.authorGuadix, Juan A
dc.contributor.authorOsorio, Fernando G
dc.contributor.authorLópez-Otín, Carlos
dc.contributor.authorHerraiz-Martínez, Adela
dc.contributor.authorCabello, Nuria
dc.contributor.authorVallmitjana, Alex
dc.contributor.authorBenítez, Raul
dc.contributor.authorGordon, Leslie B
dc.contributor.authorJalife, Jose
dc.contributor.authorPérez-Pomares, José M
dc.contributor.authorTamargo, Juan
dc.contributor.authorDelpón, Eva
dc.contributor.authorHove-Madsen, Leif
dc.contributor.authorFilgueiras-Rama, David
dc.contributor.authorAndres, Vicente
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
dc.contributor.funderInstituto de Salud Carlos III
dc.contributor.funderUnión Europea
dc.contributor.funderFundación Cajastur
dc.contributor.funderFundación ProCNIC
dc.date.accessioned2019-07-19T06:50:17Z
dc.date.available2019-07-19T06:50:17Z
dc.date.issued2016
dc.description.abstractHutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24-/- mouse model of HGPS. Challenge of Zmpste24-/- mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24-/- cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24-/- progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipSpanish Ministry of Economy and Competitiveness (MINECO) [SAF2010-16044, SAF2013-46663-R, SAF2011-30312, SAF2014-58286-C2-1-R, SAF2011-30088, SAF2014-52413-R]; Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III [RD12/0042/0028, RD12/0042/0011, RD12/0042/0002]; Fondo Europeo de Desarrollo Regional; Progeria Research Foundation; U-Mobility Grant from the Marie Curie cofunding of Regional, National and International Programme [246550]; Obra Social Cajastur; MINECO [SEV-2015-0505]; Pro CNIC Foundationes_ES
dc.format.number46es_ES
dc.format.pageE7250-E7259es_ES
dc.format.volume113es_ES
dc.identifier.citationProc Natl Acad Sci U S A. 2016; 113(46):E7250-E7259es_ES
dc.identifier.doi10.1073/pnas.1603754113es_ES
dc.identifier.e-issn1091-6490es_ES
dc.identifier.issn0027-8424es_ES
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaes_ES
dc.identifier.pubmedID27799555es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7952
dc.language.isoenges_ES
dc.publisherNational Academy of Scienceses_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2010-16044es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2013-46663-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2011-30312es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2014-58286-C2-1-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2011-30088es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2014-52413-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/0028es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/0011es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/0002es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/246550/EUes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.publisherversionhttps://doi.org/10.1073/pnas.1603754113es_ES
dc.repisalud.institucionCNICes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Fisiopatología Cardiovascular Molecular y Genéticaes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Arritmias Cardíacases_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Desarrollo Avanzado sobre Mecanismos y Terapias de las Arritmiases_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectHutchinson–Gilford progeria syndromees_ES
dc.subjectcalcium handlinges_ES
dc.subjectconnexin43es_ES
dc.subjectprelamin Aes_ES
dc.subjectprogerines_ES
dc.subject.meshAdolescentes_ES
dc.subject.meshAdultes_ES
dc.subject.meshAnimalses_ES
dc.subject.meshArrhythmias, Cardiaces_ES
dc.subject.meshCalciumes_ES
dc.subject.meshCardiac Conduction System Diseasees_ES
dc.subject.meshChildes_ES
dc.subject.meshChild, Preschooles_ES
dc.subject.meshConnexin 43es_ES
dc.subject.meshFemalees_ES
dc.subject.meshHeartes_ES
dc.subject.meshHumanses_ES
dc.subject.meshMalees_ES
dc.subject.meshMembrane Proteinses_ES
dc.subject.meshMetalloendopeptidaseses_ES
dc.subject.meshMice, Inbred C57BLes_ES
dc.subject.meshMice, Knockoutes_ES
dc.subject.meshMyocardiumes_ES
dc.subject.meshNuclear Laminaes_ES
dc.subject.meshProgeriaes_ES
dc.subject.meshSarcoplasmic Reticulumes_ES
dc.subject.meshYoung Adultes_ES
dc.titleCardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterationses_ES
dc.typejournal articlees_ES
dc.type.hasVersionAMes_ES
dspace.entity.typePublication
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