Chemerin is a new sex-specific target in aortic stenosis concomitant with diabetes regulated by the aldosterone/mineralocorticoid receptor axis

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dc.contributor.authorGoñi Olóriz, Miriam
dc.contributor.authorGaraikoetxea Zubillaga, Mattie
dc.contributor.authorSan Ildefonso-García, Susana
dc.contributor.authorFernández Celis, Amaya
dc.contributor.authorCastillo, Paula
dc.contributor.authorNavarro, Adela
dc.contributor.authorÁlvarez, Virginia
dc.contributor.authorSádaba Sagredo, Rafael
dc.contributor.authorJover, Eva
dc.contributor.authorMartín Núñez, Ernesto
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.accessioned2025-07-02T18:41:35Z
dc.date.available2025-07-02T18:41:35Z
dc.date.issued2025-01-20
dc.date.updated2025-07-02T18:22:34Z
dc.description.abstractDiabetes mellitus (DM) increases the risk of aortic stenosis (AS) and worsens its pathophysiology in a sex-specific manner. Aldosterone/mineralocorticoid receptor (Aldo/MR) pathway participates in the early stages of AS and in other diabetic-related cardiovascular complications. We aim to identify new sex-specific Aldo/MR targets in AS complicated with DM. We performed discovery studies using Olink Proteomics technology in 87 AS patient-derived aortic valves (AVs) (N ¼ 28 and N ¼ 19 nondiabetic and diabetic men; N ¼ 32 and N ¼ 8 nondiabetic and diabetic women, respectively) and human cytokine array (N ¼ 24 AVs/sex/condition). Both approaches revealed chemerin as a target differentially upregulated in AVs from male diabetic patients, further validated in a cohort of stenotic AVs (N ¼ 283, 27.6% DM, 59.4% men). Valvular chemerin levels are directly correlated with valve interstitial cell (VIC) activation, MR, inflammation, angiogenesis, and calcification markers exclusively in diabetic men. In vitro, Aldo (10-8 M) treatment exclusively increased chemerin levels in valve interstitial cells (VICs) from male patients with DM. Aldo also upregulated inflammatory, angiogenic, and osteogenic markers in DM and non-DM donors¿ VICs, which were prevented by MR antagonism. Increased glucose levels in cell media upregulated chemerin in VICs from male diabetic patients. Overall, RARRES2-knockdown in male diabetic VICs resulted in the downregulation of inflammatory, angiogenic, and osteogenic markers and blocked Aldo-induced responses in high glucose conditions. These data suggest the Aldo/MR pathway selectively increases chemerin in VICs from diabetic men, promoting inflammation, angiogenesis, and calcification associated with AS progression.en
dc.description.sponsorshipThis work was supported by the Instituto de Salud Carlos III Grant PI21/00280 and Departamento de Salud del Gobierno de Navarra Grant GNa01/21. M.G.-O. is supported by a Universidad Pública de Navarra, S.S.I.-G. by a 'Ayudas para la contratación de doctorandos y doctorandas industriales, doctorados industriales 2024' (0011-1408-2024-000006), and M.G.Z. by a Miguel Servet Foundation PhD studentships. E.J. is supported by Roche 'Stop Fuga de cerebros' 2023 and E.M.-N. by Margarita Salas postdoctoral fellowships (ULL-MS-P14, granted by Universidad de La Laguna and Ministerio de Universidades, Gobierno de España).
dc.format.mimetypeapplication/pdf
dc.identifier.citationGoñi-Olóriz, M., Zubillaga, M. G., San Ildefonso-García, S., Fernández-Celis, A., Castillo, P., Navarro, A., Álvarez, V., Sádaba, R., Jover, E., Martín-Núñez, E., López-Andrés, N. (2025) Chemerin is a new sex-specific target in aortic stenosis concomitant with diabetes regulated by the aldosterone/mineralocorticoid receptor axis. American Journal of Physiology: Heart and Circulatory Physiology, 328(3), 639-647. https://doi.org/10.1152/ajpheart.00763.2024.
dc.identifier.doi10.1152/ajpheart.00763.2024
dc.identifier.issn0363-6135
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/54378
dc.language.isoeng
dc.publisherAmerican Physiological Society
dc.relation.ispartofAmerican Journal of Physiology-Heart and Circulatory Physiology 328(3), 2025, H639-H647
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.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//0011-1408-2024-000006/
dc.relation.publisherversionhttps://doi.org/10.1152/ajpheart.00763.2024
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 stenosisen
dc.subjectChemerinen
dc.subjectDiabetesen
dc.subjectMineralocorticoid receptoren
dc.titleChemerin is a new sex-specific target in aortic stenosis concomitant with diabetes regulated by the aldosterone/mineralocorticoid receptor axisen
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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