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

Date

2022

Authors

Garaikoetxea Zubillaga, Mattie
Martín Núñez, Ernesto
Navarro, Adela
Fernández Celis, Amaya
Arrieta Paniagua, Vanessa
García Peña, Amaia
Gaínza Calleja, Alicia
Álvarez, Virginia

Director

Publisher

MDPI
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

Abstract

Aortic 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.

Description

Keywords

Aortic stenosis, Apoptosis, Calcification, FABP4, Inflammation, Sexual dimorphism, Valvular interstitial cell

Department

Ciencias de la Salud / Osasun Zientziak

Faculty/School

Degree

Doctorate program

item.page.cita

Garaikoetxea, 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/ijms23158439

item.page.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) license

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