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

Date

2025-03-01

Authors

Tiraplegui, Carolina
Garaikoetxea Zubillaga, Mattie
Sádaba, Alba
San Ildefonso-García, Susana
Fernández Celis, Amaya
Martín Núñez, Ernesto
Álvarez, Virginia
Anand, Vidhu

Director

Publisher

American Physiological Society
Acceso abierto / Sarbide irekia
Artículo / Artikulua
Versión publicada / Argitaratu den bertsioa

Project identifier

  • ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI18%2F01875/ES/ recolecta
  • ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21%2F00280/ES/ recolecta
Impacto
OpenAlexGoogle Scholar
cited by count

Abstract

Aortic 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.

Description

Keywords

Aortic regurgitation, Aortic valve, Extracellular matrix, Inflammation, Sex

Department

Ciencias de la Salud / Osasun Zientziak

Faculty/School

Degree

Doctorate program

item.page.cita

Tiraplegui, 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.

item.page.rights

© 2025 The Authors. Licensed under Creative Commons Attribution CC-BY 4.0. Published by the American Physiological Society.

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