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Targeting fatty acid-binding protein 4 improves pathologic features of aortic stenosis

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dc.contributor.authorGaraikoetxea Zubillaga, Mattiees_ES
dc.contributor.authorMartín Núñez, Ernestoes_ES
dc.contributor.authorNavarro, Adelaes_ES
dc.contributor.authorMatilla Cuenca, Lara
dc.contributor.authorFernández Celis, Amayaes_ES
dc.contributor.authorArrieta Paniagua, Vanessaes_ES
dc.contributor.authorGarcía Peña, Amaiaes_ES
dc.contributor.authorGaínza Calleja, Aliciaes_ES
dc.contributor.authorÁlvarez, Virginiaes_ES
dc.contributor.authorSádaba Sagredo, Rafaeles_ES
dc.contributor.authorJover, Evaes_ES
dc.contributor.authorLópez Andrés, Nataliaes_ES
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2022-12-29T09:27:40Z
dc.date.available2022-12-29T09:27:40Z
dc.date.issued2022
dc.date.updated2022-12-29T09:03:11Z
dc.description.abstractAortic stenosis (AS) is a fibrocalcific disease of the aortic valves (AVs). Sex-differences in AS pathophysiology have recently been described. High levels of fatty acid-binding protein 4 (FAPB4) in atherosclerotic plaques have been associated with increased local inflammation, endothelial dysfunction, and plaque vulnerability. FABP4 pharmacological blockade has been shown to be effective for the treatment of atherosclerosis by modulating metabolic and inflammatory pathways. We aimed to analyze the sex-specific expression of FABP4 in AS and its potential role as a therapeutic target. A total of 226 patients (61.5% men) with severe AS undergoing surgical AV replacement were recruited. The FABP4 levels were increased in the AVs of AS patients compared to the control subjects, showing greater expression in the fibrocalcific regions. Male AVs exhibited higher levels of FABP4 compared to females, correlating with markers of inflammation (IL-6, Rantes), apoptosis (Bax, caspase-3, Bcl-2), and calcification (IL-8, BMP-2 and BMP-4). VICs derived from AS patients showed the basal expression of FABP4 in vitro. Osteogenic media induced upregulation of intracellular and secreted FABP4 levels in male VICs after 7 days, along with increased levels of inflammatory, pro-apoptotic, and osteogenic markers. Treatment with BMS309403, a specific inhibitor of FABP4, prevented from all of these changes. Thus, we propose FABP4 as a new sex-specific pharmacological therapeutic target in AS.en
dc.description.sponsorshipThis research was funded by Miguel Servet contract CP13/00221 from the Instituto de Salud Carlos III-FEDER, Fondo de Investigaciones Sanitarias [PI18/01875; PI21/00280]. M.G. is supported by a Miguel Servet Foundation PhD studentship, E.M.-N. is supported by a Margarita Salas postdoctoral fellowship (ULL-MS-P14), L.M. is supported by a PFIS (FI19/00302) PhD studentship, E.J. (CD19/00251) is supported by a Sara Borrell postdoctoral fellowship.en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGaraikoetxea, M., Martín-Núñez, E., Navarro, A., Matilla, L., Fernández-Celis, A., Arrieta, V., García-Peña, A., Gainza, A., Álvarez, V., Sádaba, R., Jover, E., & López-Andrés, N. (2022). Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis. International Journal of Molecular Sciences, 23(15), 8439. https://doi.org/10.3390/ijms23158439en
dc.identifier.doi10.3390/ijms23158439
dc.identifier.issn1661-6596
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/44532
dc.language.isoengen
dc.publisherMDPIen
dc.relation.ispartofInternational Journal of Molecular Sciences 2022, 23, 8439en
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI18%2F01875/ES/en
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21%2F00280/ES/en
dc.relation.publisherversionhttps://doi.org/10.3390/ijms23158439
dc.rights© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) licenseen
dc.rights.accessRightsAcceso abierto / Sarbide irekiaes
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAortic stenosisen
dc.subjectApoptosisen
dc.subjectCalcificationen
dc.subjectFABP4en
dc.subjectInflammationen
dc.subjectSexual dimorphismen
dc.subjectValvular interstitial cellen
dc.titleTargeting fatty acid-binding protein 4 improves pathologic features of aortic stenosisen
dc.typeArtículo / Artikuluaes
dc.typeinfo:eu-repo/semantics/articleen
dc.type.versionVersión publicada / Argitaratu den bertsioaes
dc.type.versioninfo:eu-repo/semantics/publishedVersionen
dspace.entity.typePublication
relation.isAuthorOfPublication803d8f90-85aa-4e9f-bfa0-30454dc4e7dd
relation.isAuthorOfPublication.latestForDiscovery803d8f90-85aa-4e9f-bfa0-30454dc4e7dd

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