Met signaling in cardiomyocytes is required for normal cardiac function in adult mice

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dc.contributor.authorArechederra Calderón, María
dc.contributor.authorCarmona Mejías, Rita
dc.contributor.authorGonzález-Nuñez, María
dc.contributor.authorGutiérrez Uzquiza, Álvaro
dc.contributor.authorBragado Domingo, Paloma
dc.contributor.authorCruz-González, Ignacio
dc.contributor.authorCano Rincón, Elena
dc.contributor.authorGuerrero Arroyo, María Del Carmen
dc.contributor.authorSánchez Muñoz, Aranzazu
dc.contributor.authorLópez-Novoa, José Miguel
dc.contributor.authorSchneider, Michael D.
dc.contributor.authorMaina, Flavio
dc.contributor.authorMuñoz-Chápuli, Ramón
dc.contributor.authorPorras Gallo, María Almudena
dc.date.accessioned2024-02-08T08:54:44Z
dc.date.available2024-02-08T08:54:44Z
dc.date.issued2013
dc.description.abstractHepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-α-MHC mouse line (referred to as α-MHCMet-KO). Although α-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6 months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as β-MHC and ANF, was also observed. By the age of 9 months, α-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in α-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-β production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in α-MHCMet-KO mice. Consistently, we show that HGF acts through p38α to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Farmacia
dc.description.refereedTRUE
dc.description.sponsorshipAssociation Française contre les myopathies
dc.description.sponsorshipMinisterio de Ciencia, Innovación y Universidades (España)
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipUniversidad Complutense de Madrid
dc.description.sponsorshipJunta de Andalucía
dc.description.sponsorshipFondation pour la Recherche Médicale
dc.description.sponsorshipFondation Bettencourt-Schueller
dc.description.statuspub
dc.identifier.citationArechederra M, Carmona R, González-Nuñez M, Gutiérrez-Uzquiza Á, Bragado P, Cruz-González I, et al. Met signaling in cardiomyocytes is required for normal cardiac function in adult mice. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2013;1832:2204–15. https://doi.org/10.1016/j.bbadis.2013.08.008.
dc.identifier.doi10.1016/j.bbadis.2013.08.008
dc.identifier.issn0925-4439
dc.identifier.officialurlhttps://doi.org/10.1016/j.bbadis.2013.08.008
dc.identifier.urihttps://hdl.handle.net/20.500.14352/100200
dc.journal.titleBiochimica et Biophysica Acta (Molecular Basis of disease)
dc.language.isoeng
dc.page.final2215
dc.page.initial2204
dc.relation.projectIDinfo:eu-repo/grantAgreement/FIS-PI07/0071
dc.relation.projectIDinfo:eu-repo/grantAgreement/SAF-2010-20198-C02-01
dc.relation.projectIDinfo:eu-repo/grantAgreement/CAM/UCM 920384
dc.relation.projectIDinfo:eu-repo/grantAgreement/UCM-BSCH 920384
dc.relation.projectIDinfo:eu-repo/grantAgreement/BFU2011-25304
dc.relation.projectIDinfo:eu-repo/grantAgreement/RD12/0019/0022
dc.relation.projectIDinfo:eu-repo/grantAgreement/P11-CTS-7564
dc.relation.projectIDinfo:eu-repo/grantAgreement/SAF2010- 15881
dc.relation.projectIDRD012/ M. Arechederra et al. / Biochimica et Biophysica Acta 1832 (2013) 2204–2215 2213 0021
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu577.1
dc.subject.keywordMet
dc.subject.keywordp38MAPK
dc.subject.keywordOxidative stress
dc.subject.keywordHepatocyte growth factor
dc.subject.keywordCardiomyocytes
dc.subject.keywordHeart
dc.subject.ucmBioquímica (Química)
dc.subject.unesco2302 Bioquímica
dc.titleMet signaling in cardiomyocytes is required for normal cardiac function in adult mice
dc.typejournal article
dc.type.hasVersionAM
dc.volume.number1832
dspace.entity.typePublication
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