Goñi Olóriz, Miriam

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https://academica-e.unavarra.es/handle/2454/53548

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Goñi Olóriz

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Miriam

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Ciencias de la Salud

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1355071

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813193

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2023 - 20254
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Author: Garaikoetxea Zubillaga, Mattie × Has files: true ×

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  • Thumbnail Image
    PublicationOpen Access
    Chemerin is a new sex-specific target in aortic stenosis concomitant with diabetes regulated by the aldosterone/mineralocorticoid receptor axis
    (American Physiological Society, 2025-01-20) Goñi Olóriz, Miriam; Garaikoetxea Zubillaga, Mattie; San Ildefonso-García, Susana; Fernández Celis, Amaya; Castillo, Paula; Navarro, Adela; Álvarez, Virginia ; Sádaba Sagredo, Rafael; Jover, Eva; Martín Núñez, Ernesto; López Andrés, Natalia; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
    Diabetes 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.
  • Thumbnail Image
    PublicationOpen Access
    The presence of adipose tissue in aortic valves influences inflammation and extracellular matrix composition in chronic aortic regurgitation
    (MDPI, 2025-03-28) Sádaba, Alba; Garaikoetxea Zubillaga, Mattie; Tiraplegui, Carolina; San Ildefonso-García, Susana; Goñi Olóriz, Miriam; Fernández Celis, Amaya; Martín Núñez, Ernesto; Castillo, Paula; Álvarez, Virginia; Sádaba Sagredo, Rafael; Jover, Eva; Navarro, Adela; López Andrés, Natalia; Ciencias de la Salud; Osasun Zientziak
    Adipose tissue is present in aortic valves (AVs). Valve interstitial cells (VICs) could differentiate into adipogenic lineages. We here characterize whether the presence of adipose tissue in the AV influences inflammation and extracellular matrix (ECM) composition in patients with aortic regurgitation (AR). A total of 144 AVs were analyzed by histological and molecular techniques. We performed discovery studies using Olink Proteomics® technology in 40 AVs (N = 16 without and N = 24 with adipose tissue). In vitro, human white adipocytes (HWAs) or VICs were cultured with adipogenic media and co-cultured with control VICs. Of Avs, 67% presented white-like adipocytes within the spongiosa. Discovery studies revealed increased levels of inflammatory and ECM molecules in AVs containing adipocytes. Interestingly, the presence of adipocytes was associated with greater AV thickness, higher inflammation, and ECM remodeling, which was characterized by increased proinflammatory molecules, collagen, fibronectin, proteoglycans, and metalloproteinases. AV thickness positively correlated with markers of adipose tissue, inflammation, and ECM. In vitro, adipocyte-like VICs expressed higher levels of adipocyte markers, increased cytokines, fibronectin, decorin, and MMP-13. Analyses of supernatants from co-cultured control VICs with HWA or adipocyte-like VICs showed higher expression of inflammatory mediators, collagen type I, proteoglycans, and metalloproteinases. AVs presenting adipocytes were thicker and exhibited changes characterized by increased inflammation accompanied by aberrant expression of collagen, proteoglycans, and metalloproteinases. VICs could differentiate into adipogenic pathway, affect neighbor VICs, and contribute to inflammation, collagen and proteoglycan accumulation, as well as to metalloproteinases secretion. In summary, the presence of adipose tissue in AV could modify its composition, favoring inflammation and remodeling with an impact on AV thickness.
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    PublicationOpen Access
    Influence of diabetes mellitus on the pathological profile of aortic stenosis: a sex-based approach
    (Springer Nature, 2023) Martín Núñez, Ernesto; Goñi Olóriz, Miriam; Matilla Cuenca, Lara; Garaikoetxea Zubillaga, Mattie; Mourino-Álvarez, Laura; Navarro, Adela; Fernández Celis, Amaya; Tamayo Rodríguez, Ibai; Gaínza Calleja, Alicia; Álvarez, Virginia; Sádaba Sagredo, Rafael; Barderas, María G.; Jover, Eva; López Andrés, Natalia; Ciencias de la Salud; Osasun Zientziak
    Background: Diabetes mellitus (DM) accelerates the progression of aortic stenosis (AS), but how their underlying molecular mechanisms interact is not clear. Moreover, whether DM contributes to clinically relevant sex-differences in AS is unknown. In this work we aim to characterize the sex-specific profile of major pathological mechanisms fundamental to aortic valve (AV) degeneration in AS patients with or without concomitant DM. Methods: 283 patients with severe AS undergoing surgical valve replacement (27.6% DM, 59.4% men) were recruited. Expression of pathological markers related to AS were thoroughly assessed in AVs and valve interstitial cells (VICs) according to sex and presence of DM. Complementary in vitro experiments in VICs in the presence of high-glucose levels (25 mM) for 24, 48 and 72 h were performed. Results: Oxidative stress and metabolic dysfunction markers were increased in AVs from diabetic AS patients compared to non-diabetic patients in both sexes. However, disbalanced oxidative stress and enhanced inflammation were more predominant in AVs from male AS diabetic patients. Osteogenic markers were exclusively increased in the AVs of diabetic women. Basal characterization of VICs confirmed that oxidative stress, inflammation, calcification, and metabolic alteration profiles were increased in diabetic VICs with sex-specific differences. VICs cultured in hyperglycemic-like conditions triggered inflammatory responses in men, whereas in women rapid and higher production of pro-osteogenic molecules. Conclusions: DM produces sex-specific pathological phenotypes in AV of AS patients. Importantly, women with diabetes are more prone to develop AV calcification. DM should be considered as a risk factor in AS especially in women.
  • Thumbnail Image
    PublicationOpen Access
    Sex differences in aortic valve inflammation and remodeling in chronic severe aortic regurgitation
    (American Physiological Society, 2025-03-01) Tiraplegui, Carolina; Garaikoetxea Zubillaga, Mattie; Sádaba, Alba ; San Ildefonso-García, Susana; Goñi Olóriz, Miriam; Fernández Celis, Amaya; Martín Núñez, Ernesto; Álvarez, Virginia; Sádaba Sagredo, Rafael; Anand, Vidhu; Jover, Eva; Navarro, Adela; López Andrés, Natalia; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
    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.