Person: Matilla Cuenca, Lara
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Matilla Cuenca
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Lara
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Ciencias de la Salud
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0000-0002-4234-8529
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811776
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Publication Open Access Sex-specific role of galectin-3 in aortic stenosis(BMC, 2023) Matilla Cuenca, Lara; Martín Núñez, Ernesto; Garaikoetxea Zubillaga, Mattie; Navarro, Adela; Tamayo Rodríguez, Ibai; Fernández Celis, Amaya; Gaínza Calleja, Alicia; Fernández Irigoyen, Joaquín; Santamaría, Enrique; Muntendam, Pieter; Álvarez, Virginia; Sádaba Sagredo, Rafael; Jover, Eva; López Andrés, Natalia; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate PublikoaBackground: Aortic stenosis (AS) is characterized by infammation, fbrosis, osteogenesis and angiogenesis. Men and women develop these mechanisms diferently. Galectin-3 (Gal-3) is a pro-infammatory and pro-osteogenic lectin in AS. In this work, we aim to analyse a potential sex-diferential role of Gal-3 in AS. Methods: 226 patients (61.50% men) with severe AS undergoing surgical aortic valve (AV) replacement were recruited. In AVs, Gal-3 expression and its relationship with infammatory, osteogenic and angiogenic markers was assessed. Valve interstitial cells (VICs) were primary cultured to perform in vitro experiments. Results: Proteomic analysis revealed that intracellular Gal-3 was over-expressed in VICs of male AS patients. Gal-3 secretion was also higher in men’s VICs as compared to women’s. In human AVs, Gal-3 protein levels were signifcantly higher in men, with stronger immunostaining in VICs with myofbroblastic phenotype and valve endothelial cells. Gal-3 levels in AVs were positively correlated with infammatory markers in both sexes. Gal-3 expression was also posi tively correlated with osteogenic markers mainly in men AVs, and with angiogenic molecules only in this sex. In vitro, Gal-3 treatment induced expression of infammatory, osteogenic and angiogenic markers in male’s VICs, while it only upregulated infammatory and osteogenic molecules in women-derived cells. Gal-3 blockade with pharma cological inhibitors (modifed citrus pectin and G3P-01) prevented the upregulation of infammatory, osteogenic and angiogenic molecules. Conclusions: Gal-3 plays a sex-diferential role in the setting of AS, and it could be a new sex-specifc therapeutic target controlling pathological features of AS in VICs.Publication Open Access Targeting fatty acid-binding protein 4 improves pathologic features of aortic stenosis(MDPI, 2022) Garaikoetxea Zubillaga, Mattie; Martín Núñez, Ernesto; Navarro, Adela; Matilla Cuenca, Lara; Fernández Celis, Amaya; Arrieta Paniagua, Vanessa; García Peña, Amaia; Gaínza Calleja, Alicia; Álvarez, Virginia; Sádaba Sagredo, Rafael; Jover, Eva; López Andrés, Natalia; Ciencias de la Salud; Osasun ZientziakAortic 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.Publication Open Access Sex-dependent expression of neutrophil gelatinase-associated lipocalin in aortic stenosis(BMC, 2022) Jover, Eva; Matilla Cuenca, Lara; Martín Núñez, Ernesto; Garaikoetxea Zubillaga, Mattie; Navarro, Adela; Fernández Celis, Amaya; Gaínza Calleja, Alicia; Arrieta Paniagua, Vanessa; García Peña, Amaia; Álvarez, Virginia; Sádaba Sagredo, Rafael; Jaisser, Frederic; López Andrés, Natalia; Ciencias de la Salud; Osasun ZientziakBackground: Accumulating evidence suggest the existence of sex-related differences in the pathogenesis of aortic stenosis (AS) with inflammation, oxidative stress, fibrosis and calcification being over-represented in men. Neutrophil gelatinase-associated lipocalin (NGAL) is expressed in a myriad of tissues and cell types, and it is associated with acute and chronic pathological processes comprising inflammation, fibrosis or calcification. Sex-dependent signatures have been evidenced for NGAL which expression has been associated predominantly in males to metabolic and cardiovascular disorders. We aimed to analyse sex-related differences of NGAL in AS and its role in the inflammatory and fibrocalcific progression of AS. Methods and results: 220 (60.45% men) patients with severe AS elective for surgical aortic valve (AV) replacement were recruited. Immunohistochemistry revealed higher expression of NGAL in calcific areas of AVs and that was validated by qPCR in in 65 (60% men) donors. Valve interstitial cells (VICs) were a source of NGAL in these samples. Proteome profiler analyses evidenced higher expression of NGAL in men compared to women, and that was further validated by ELISA. NGAL expression in the AV was correlated with inflammation, oxidative stress, and osteogenic markers, as well as calcium score. The expression of NGAL, both intracellular and secreted (sNGAL), was significantly deregulated only in calcifying male-derived VICs. Depletion of intracellular NGAL in calcifying male-derived VICs was associated with pro-inflammatory profiles, dysbalanced matrix remodelling and pro-osteogenic profiles. Conversely, exogenous NGAL mediated inflammatory and dysbalanced matrix remodelling in calcifying VICs, and all that was prevented by the pharmacological blockade of NGAL. Conclusions: Owing to the over-expression of NGAL, the AV from men may be endowed with higher expression of inflammatory, oxidative stress, matrix remodelling and osteogenic markers supporting the progression of calcific AS phenotypes. The expression of NGAL in the VIC emerges as a potential therapeutic checkpoint, with its effects being potentially reverted by the pharmacological blockade of extracellular NGAL.