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Título:
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Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function
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Autor/a:
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McDermott Roe, Chris; Ye, Junmei; Ahmed, Rizwan; Sun, Xi-Ming; Serafín, Anna; Ware, James; Bottolo, Leonardo; Muckett, Phil; Cañas, Xavier; Zhang, Jisheng; Rowe, Glenn C.; Buchan, Rachel; Lu, Han; Braithwaite, Adam; Mancini, Massimiliano; Hauton, David; Martí, Ramon; García Arumí, Elena; Hubner, Norbert; Jacob, Howard; Serikawa, Tadao; Zidek, Vaclav; Papousek, Frantisek; Kolar, Frantisek; Cardona Colom, Maria; Ruiz Meana, Marisol; García Dorado, David; Comella i Carnicé, Joan Xavier; Felkin, Leanne E.; Barton, Paul J. R.; Zoltan Arany; Pravenec, Michal; Petretto, Enrico; Sanchis, Daniel; Cook, Stuart A.
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Notas:
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Left 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.
We 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. |
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Materia(s):
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-Genetics and genomics
-Disease
-Cell biology |
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Derechos:
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(c) Macmillan Publishers Limited, 2011
info:eu-repo/semantics/restrictedAccess |
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Tipo de documento:
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article
publishedVersion |
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Editor:
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Macmillan Publishers Limited
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