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dc.contributor.authorOller, Jorge 
dc.contributor.authorMendez-Barbero, Nerea 
dc.contributor.authorRuiz, E Josue 
dc.contributor.authorVillahoz, Silvia 
dc.contributor.authorRenard, Marjolijn
dc.contributor.authorCanelas, Lizet I 
dc.contributor.authorBriones, Ana M
dc.contributor.authorAlberca, Rut 
dc.contributor.authorLozano-Vidal, Noelia 
dc.contributor.authorHurlé, María A
dc.contributor.authorMilewicz, Dianna
dc.contributor.authorEvangelista, Arturo
dc.contributor.authorSalaices, Mercedes
dc.contributor.authorNistal, J Francisco
dc.contributor.authorJimenez-Borreguero, Luis J. 
dc.contributor.authorDe Backer, Julie
dc.contributor.authorCampanero, Miguel R
dc.contributor.authorRedondo, Juan Miguel 
dc.date.accessioned2018-12-21T10:05:38Z
dc.date.available2018-12-21T10:05:38Z
dc.date.issued2017-02
dc.identifier.citationNat Med. 2017; 23(2):200-212es_ES
dc.identifier.issn1078-8956es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/6924
dc.description.abstractHeritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology. Pharmacological inhibition of Nos2 rapidly reversed aortic dilation and medial degeneration in young Adamts1-deficient mice and in young or old MFS mice. Patients with MFS showed elevated NOS2 and decreased ADAMTS1 protein levels in the aorta. These findings uncover a possible causative role for the ADAMTS1-NOS2 axis in human TAAD and warrant evaluation of NOS2 inhibitors for therapy.es_ES
dc.description.sponsorshipCNIC is supported by the Spanish Ministerio de Economía, Industria y Competitividad (MINECO) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Support was also provided by grants from MINECO (grants SAF2013-45258P (M.R.C.), SAF2012-34296 (J.M.R.) and SAF2015-636333R (J.M.R.)), Fundacion La Marato (TV3 grants 20151331 (J.M.R.) and 20151330 (A.E.)), CSIC (M.R.C.), the CIBERCV of Ministerio de Sanidad (grant CB16/11/00264; J.M.R.) and the Red de Investigación Cardiovascular (RIC) of Ministerio de Sanidad (grants RD12/0042/0022 (J.M.R.), RD12/0042/0021 (A.E.), RD12/0042/0024 (M.S.), RD12/0042/0056 (J.L.J.-B.) and RD12/0042/0018 (J.F.N.)), and by a Marie Skłodowska-Curie fellowship (E.J.R.) and FPI fellowships BES 2010-034552 (J.O.) and SVP-2013-067777 (S.V.). The cost of this publication has been paid in part with FEDER funds.es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Groupes_ES
dc.relation.isversionofPostprintes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshADAMTS1 Protein es_ES
dc.subject.meshAdult es_ES
dc.subject.meshAged es_ES
dc.subject.meshAneurysm, Dissecting es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshAorta es_ES
dc.subject.meshAortic Aneurysm es_ES
dc.subject.meshAortic Aneurysm, Thoracic es_ES
dc.subject.meshDisease Models, Animales_ES
dc.subject.meshEnzyme Inhibitors es_ES
dc.subject.meshFemale es_ES
dc.subject.meshFibrillin-1 es_ES
dc.subject.meshGene Knockdown Techniques es_ES
dc.subject.meshHaploinsufficiency es_ES
dc.subject.meshHumans es_ES
dc.subject.meshImmunoblotting es_ES
dc.subject.meshMale es_ES
dc.subject.meshMarfan Syndrome es_ES
dc.subject.meshMice es_ES
dc.subject.meshMiddle Aged es_ES
dc.subject.meshNG-Nitroarginine Methyl Ester es_ES
dc.subject.meshNitric Oxide es_ES
dc.subject.meshNitric Oxide Synthase Type II es_ES
dc.subject.meshReal-Time Polymerase Chain Reaction es_ES
dc.titleNitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndromees_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID28067899es_ES
dc.format.volume23es_ES
dc.format.number2es_ES
dc.format.page200-212es_ES
dc.identifier.doi10.1038/nm.4266es_ES
dc.contributor.funderMinisterio de Economía, Competitividad e Industria (España)es_ES
dc.contributor.funderFundación ProCNICes_ES
dc.contributor.funderFundacio la Maratoes_ES
dc.contributor.funderRed de Investigación Cardiovascular (España)es_ES
dc.contributor.funderCentro de Investigación Biomedica en Red - CIBERes_ES
dc.contributor.funderMinisterio de Sanidad (España)es_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1546-170Xes_ES
dc.relation.publisherversionhttps://doi.org/10.1038/nm.4266es_ES
dc.identifier.journalNature medicinees_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Génica en Remodelado Vascular e Inflamaciónes_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2013-45258Pes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2012-34296es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2015-636333Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/B16/11/00264es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/0022es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/0021es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/0024es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/0056es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0042/0018es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BES-2010-034552es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SVP-2013-067777es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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