Sex differences in aortic valve inflammation and remodeling in chronic severe aortic regurgitation

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dc.contributor.authorTiraplegui, Carolina
dc.contributor.authorGaraikoetxea Zubillaga, Mattie
dc.contributor.authorSádaba, Alba
dc.contributor.authorSan Ildefonso-García, Susana
dc.contributor.authorGoñi Olóriz, Miriam
dc.contributor.authorFernández Celis, Amaya
dc.contributor.authorMartín Núñez, Ernesto
dc.contributor.authorÁlvarez, Virginia
dc.contributor.authorSádaba Sagredo, Rafael
dc.contributor.authorAnand, Vidhu
dc.contributor.authorJover, Eva
dc.contributor.authorNavarro, Adela
dc.contributor.authorLópez Andrés, Natalia
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.funderGobierno de Navarra / Nafarroako Gobernua
dc.date.accessioned2025-06-30T13:26:05Z
dc.date.available2025-06-30T13:26:05Z
dc.date.issued2025-03-01
dc.date.updated2025-06-30T12:58:24Z
dc.description.abstractAortic regurgitation (AR) is more prevalent in males, although cellular and molecular mechanisms underlying the sex differences in prevalence and pathophysiology are unknown. This study evaluates the impact of sex on aortic valve (AV) inflammation and remodeling and the cellular differences in valvular interstitial cells (VICs) and valvular endothelial cells (VECs) in patients with AR. A total of 144 patients (27.5% female) with severe chronic AR were included. AVs were analyzed by imaging, histological, and molecular biology techniques (ELISA, RT-PCR). VICs and VECs isolated from patients with AR were characterized and further treated with transforming growth factor (TGF)-β. Anatomically, male had smaller index aortic dimensions and greater AV thickness. Proteome profiler analyzes in AVs (n = 40/sex) evidenced higher expression of inflammatory markers in male and that was further validated (interleukins, chemokines). Histological composition showed higher expression of inflammatory mediators and collagen thick fibers in AVs from male. Male VICs and VECs secreted higher levels of inflammatory markers than female cells. Interestingly, male VICs produced higher amounts of collagen type I and lower fibronectin and aggrecan, whereas male VECs secreted lower decorin. TGF-β exclusively enhanced inflammation in male VICs and decorin and aggrecan in female VICs. Compared with male, AVs from female were thinner, less inflamed, and fibrotic. VICs seem to be the key cell type responsible for the sex-differences. Valvular inflammation associated with an active remodeling process could be a key pathophysiological process involved in AR.en
dc.description.sponsorshipThis research was funded by Fondo de Investigaciones Sanitarias under Grant Nos. PI18/01875; PI21/00280 from Instituto de Salud Carlos III-FEDER and BIOGEN (PC020-021-022) from Ayudas a Agentes del SINAI para la realización de proyectos de I+D colaborativos del Gobierno de Navarra. 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 and E.J. (CD19/00251) was supported by a Sara Borrell postdoctoral fellowship and by a Roche 'Stop Fuga de cerebros' postdoctoral fellowship. This study was also funded by the Departamento de Salud del Gobierno de Navarra Grant GºNa01/21.
dc.format.mimetypeapplication/pdf
dc.identifier.citationTiraplegui, C., Garaikoetxea, M., Sádaba, A., San Ildefonso-García, S., Goñi-Olóriz, M., Fernández-Celis, A., Martín-Núñez, E., Álvarez, V., Sádaba, R., Anand, V., Jover, E., Navarro, A., López-Andrés, N. (2025) Sex differences in aortic valve inflammation and remodeling in chronic severe aortic regurgitation. American Journal of Physiology: Heart and Circulatory Physiology, 328(3), 693-710. https://doi.org/10.1152/ajpheart.00645.2024.
dc.identifier.doi10.1152/ajpheart.00645.2024
dc.identifier.issn0363-6135
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/54348
dc.language.isoeng
dc.publisherAmerican Physiological Society
dc.relation.ispartofAmerican Journal of Physiology: Heart and Circulatory Physiology 328(3), 2025, H693-H710
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI18%2F01875/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21%2F00280/ES/
dc.relation.publisherversionhttps://doi.org/10.1152/ajpheart.00645.2024
dc.rights© 2025 The Authors. Licensed under Creative Commons Attribution CC-BY 4.0. Published by the American Physiological Society.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAortic regurgitationen
dc.subjectAortic valveen
dc.subjectExtracellular matrixen
dc.subjectInflammationen
dc.subjectSexen
dc.titleSex differences in aortic valve inflammation and remodeling in chronic severe aortic regurgitationen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication919e6260-466a-40a4-aded-bfbf1549d7b8
relation.isAuthorOfPublication23d03177-1c69-4293-bfd4-1de28bf3c05b
relation.isAuthorOfPublication.latestForDiscovery919e6260-466a-40a4-aded-bfbf1549d7b8

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