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dc.contributor.authorMolina-Sanchez, Pedro 
dc.contributor.authorChevre, Raphael 
dc.contributor.authorRius, Cristina 
dc.contributor.authorFuster, Jose J. 
dc.contributor.authorAndres, Vicente 
dc.date.accessioned2019-07-17T08:21:59Z
dc.date.available2019-07-17T08:21:59Z
dc.date.issued2015-07
dc.identifier.citationJ Mol Cell Cardiol. 2015; 84:84-94es_ES
dc.identifier.issn00222828es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7924
dc.description.abstractReduced phosphorylation of the tumor suppressor p27(Kip1) (p27) at serine 10 (Ser10) is a hallmark of advanced human and mouse atherosclerosis. Apolipoprotein E-null mice defective for this posttranslational modification (apoE(-/-)p27Ser10Ala) exhibited increased atherosclerosis burden at late disease states. Here, we investigated the regulation of p27 phosphorylation in Ser10 at the very initial stages of atherosclerosis and its impact on endothelial-leukocyte interaction and early plaque formation. Hypercholesterolemia in fat-fed apoE(-/-) mice is associated with a rapid downregulation of p27-phospho-Ser10 in primary endothelial cells (ECs) and in aorta prior to the development of macroscopically-visible lesions. We find that lack of p27 phosphorylation at Ser10 enhances the expression of adhesion molecules in aorta of apoE(-/-) mice and ECs, and augments endothelial-leukocyte interactions and leukocyte recruitment in vivo. These effects correlated with increased RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) signaling in ECs, and inhibition of this pathway with fasudil reduced leukocyte-EC interactions to control levels in the microvasculature of p27Ser10Ala mice. Moreover, apoE(-/-)p27Ser10Ala mice displayed increased leukocyte recruitment and homing to atherosusceptible arteries and augmented early plaque development, which could be blunted with fasudil. In conclusion, our studies demonstrate a very rapid reduction in p27-phospho-Ser10 levels at the onset of atherogenesis, which contributes to early plaque build-up through RhoA/ROCK-induced integrin expression in ECs and enhanced leukocyte recruitment.es_ES
dc.description.sponsorshipSpanish Ministry of Economy and Competitivity (MINECO) [SAF2010-16044, SAF2013-46663-R]; Fondo Europeo de Desarrollo Regional (FEDER); Instituto de Salud Carlos III [RD12/0042/0028]; FPU predoctoral fellowship from MINECO; MINECO; Pro-CNIC Foundationes_ES
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.relation.isversionofPostprintes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAtherosclerosises_ES
dc.subjectEndothelial celles_ES
dc.subjectLeukocyte recruitmentes_ES
dc.subjectRhoAes_ES
dc.subjectp27es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshAorta es_ES
dc.subject.meshApolipoproteins E es_ES
dc.subject.meshArterioles es_ES
dc.subject.meshAtherosclerosis es_ES
dc.subject.meshCell Adhesion es_ES
dc.subject.meshCells, Cultured es_ES
dc.subject.meshCyclin-Dependent Kinase Inhibitor p27 es_ES
dc.subject.meshDiet es_ES
dc.subject.meshEndothelial Cells es_ES
dc.subject.meshEnzyme Activation es_ES
dc.subject.meshHypercholesterolemia es_ES
dc.subject.meshLeukocytes es_ES
dc.subject.meshMice, Inbred C57BL es_ES
dc.subject.meshPhosphorylation es_ES
dc.subject.meshPhosphoserine es_ES
dc.subject.meshPlaque, Atherosclerotices_ES
dc.subject.meshSignal Transduction es_ES
dc.subject.meshVascular Cell Adhesion Molecule-1 es_ES
dc.subject.meshrho-Associated Kinases es_ES
dc.subject.meshrhoA GTP-Binding Protein es_ES
dc.titleLoss of p27 phosphorylation at Ser10 accelerates early atherogenesis by promoting leukocyte recruitment via RhoA/ROCKes_ES
dc.typeArtículoes_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.identifier.pubmedID25908026es_ES
dc.format.volume84es_ES
dc.format.page84-94es_ES
dc.identifier.doi10.1016/j.yjmcc.2015.04.013es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.contributor.funderInstituto de Salud Carlos III - ISCIIIes_ES
dc.contributor.funderFundación ProCNICes_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1095-8584es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.yjmcc.2015.04.013es_ES
dc.identifier.journalJournal of molecular and cellular cardiologyes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Fisiopatología Cardiovascular Molecular y Genéticaes_ES
dc.repisalud.institucionCNICes_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/RD12/0042/0028es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
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