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dc.contributor.authorMcDermott Roe, Chris
dc.contributor.authorYe, Junmei
dc.contributor.authorAhmed, Rizwan
dc.contributor.authorSun, Xi-Ming
dc.contributor.authorSerafín, Anna
dc.contributor.authorWare, James
dc.contributor.authorBottolo, Leonardo
dc.contributor.authorMuckett, Phil
dc.contributor.authorCañas, Xavier
dc.contributor.authorZhang, Jisheng
dc.contributor.authorRowe, Glenn C.
dc.contributor.authorBuchan, Rachel
dc.contributor.authorLu, Han
dc.contributor.authorBraithwaite, Adam
dc.contributor.authorMancini, Massimiliano
dc.contributor.authorHauton, David
dc.contributor.authorMartí, Ramon
dc.contributor.authorGarcía Arumí, Elena
dc.contributor.authorHubner, Norbert
dc.contributor.authorJacob, Howard
dc.contributor.authorSerikawa, Tadao
dc.contributor.authorZidek, Vaclav
dc.contributor.authorPapousek, Frantisek
dc.contributor.authorKolar, Frantisek
dc.contributor.authorCardona Colom, Maria
dc.contributor.authorRuiz Meana, Marisol
dc.contributor.authorGarcía Dorado, David
dc.contributor.authorComella i Carnicé, Joan Xavier
dc.contributor.authorFelkin, Leanne E.
dc.contributor.authorBarton, Paul J. R.
dc.contributor.authorZoltan Arany
dc.contributor.authorPravenec, Michal
dc.contributor.authorPetretto, Enrico
dc.contributor.authorSanchis, Daniel
dc.contributor.authorCook, Stuart A.
dc.date.accessioned2016-11-23T10:43:36Z
dc.date.issued2011
dc.identifier.issn0028-0836
dc.identifier.urihttp://hdl.handle.net/10459.1/58625
dc.description.abstractLeft ventricular mass (LVM) is a highly heritable trait1 and an independent risk factor for all-cause mortality2. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation3, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood4, 5. Unbiased systems genetics approaches in the rat6, 7 now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis8 but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function)9, 10, 11, interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.ca_ES
dc.description.sponsorshipWe acknowledge funding from the Medical Research Council (UK), theNational Institute for Health Research (UK), the Royal Brompton andHarefield Cardiovascular Biomedical Research Unit, the Imperial College Healthcare Biomedical Research Centre, the British Heart Foundation, Fondation Leducq, the Wellcome Trust, the Grant Agency of the Czech Republic (301/08/0166), the Ministry of Education of the Czech Republic (1M0520), the Ministerio de Ciencia e Innovacion (Spain; PTQ-08-03-07880, SAF2008-02271, SAF2008-03067 and SAF2010-19125), the Agència de Gestió d’AjutsUniversitaris i Recerca (Spain; 2009-SGR-346), the Fondo de Investigaciones Sanitarias (Spain; PS09/02034, PS09/01602 and PS09/01591), the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. HEALTH-F4-2010-241504 (EURATRANS), and the German National Genome Research Network (NGFN-Plus) Heart Failure. We thank M. R. Lieber for providing the Endog deleted mice and E. Wahle for providing the CG4930 expression plasmid. We thank the National BioResource Project for the Rat (http:// www.anim.med.kyoto-u.ac.jp/NBR/) for providing rat strains.ca_ES
dc.language.isoengca_ES
dc.publisherMacmillan Publishers Limitedca_ES
dc.relationMICINN/PN2008-2011/SAF2008-02271
dc.relationMICINN/PN2008-2011/SAF2008-03067
dc.relationMICINN/PN2008-2011/SAF2010-19125
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1038/nature10490ca_ES
dc.relation.ispartofNature , 2011, vol. 478, p. 114-118ca_ES
dc.rights(c) Macmillan Publishers Limited, 2011ca_ES
dc.subjectGenetics and genomicsca_ES
dc.subjectDiseaseca_ES
dc.subjectCell biologyca_ES
dc.titleEndonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial functionca_ES
dc.typearticleca_ES
dc.identifier.idgrec018063
dc.type.versionpublishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccessca_ES
dc.identifier.doihttps://doi.org/10.1038/nature10490
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/241504
dc.date.embargoEndDate2025-01-01


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