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© 2021 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 (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Graves’ disease (GD) is an autoimmune thyroiditis often associated with Graves’ orbitopathy (GO). GD thyroid and GO orbital fat share high oxidative stress (OS) and hypervascularization. We investigated the metabolic pathways leading to OS and angiogenesis, aiming to further decipher the link between local and systemic GD manifestations. Plasma and thyroid samples were obtained from patients operated on for multinodular goiters (controls) or GD. Orbital fats were from GO or control patients. The NADPH-oxidase-4 (NOX4)/HIF-1α/VEGF-A signaling pathway was investigated by Western blotting and immunostaining. miR-199a family expression was evaluated following quantitative real-time PCR and/or in situ hybridization. In GD thyroids and GO orbital fats, NOX4 was upregulated and correlated with HIF-1α stabilization and VEGF-A overexpression. The biotin assay identified NOX4, HIF-1α and VEGF-A as direct targets of miR-199a-5p in cultured thyrocytes. Interestingly, GD thyroids, GD plasmas and GO orbital fats showed a downregulation of miR-199a-3p/-5p. Our results also highlighted an activation of STAT-3 signaling in GD thyroids and GO orbital fats, a transcription factor known to negatively regulate miR-199a expression. We identified NOX4/HIF-1α/VEGF-A as critical actors in GD and GO. STAT-3-dependent regulation of miR-199a is proposed as a common driver leading to these events in GD thyroids and GO orbital fats.

Details

Title
miR-199a Downregulation as a Driver of the NOX4/HIF-1α/VEGF-A Pathway in Thyroid and Orbital Adipose Tissues from Graves′ Patients
Author
Craps, Julie 1   VIAFID ORCID Logo  ; Joris, Virginie 2 ; Baldeschi, Lelio 3 ; Daumerie, Chantal 4 ; Camboni, Alessandra 5 ; Buemi, Antoine 6 ; Lengelé, Benoit 7 ; Behets, Catherine 8   VIAFID ORCID Logo  ; Boschi, Antonella 3 ; Mourad, Michel 6 ; Many, Marie-Christine 8 ; Dessy, Chantal 2   VIAFID ORCID Logo 

 Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium; [email protected] (J.C.); [email protected] (V.J.); Pole of Morphology, Institute of Experimental and Clinical Research (IREC), UCLouvain, B-1200 Brussels, Belgium; [email protected] (B.L.); [email protected] (C.B.); [email protected] (M.-C.M.) 
 Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium; [email protected] (J.C.); [email protected] (V.J.) 
 Department of Ophthalmology, Cliniques Universitaires Saint Luc, UCLouvain, B-1200 Brussels, Belgium; [email protected] (L.B.); [email protected] (A.B.) 
 Departement of Endocrinology, Cliniques Universitaires Saint Luc, UCLouvain, B-1200 Brussels, Belgium; [email protected] 
 Departement of Anatomopathology, Cliniques Universitaires Saint Luc, UCLouvain, B-1200 Brussels, Belgium; [email protected] 
 Departement of Surgery and Abdominal Transplantation, Cliniques Universitaires Saint Luc, UCLouvain, B-1200 Brussels, Belgium; [email protected] (A.B.); [email protected] (M.M.) 
 Pole of Morphology, Institute of Experimental and Clinical Research (IREC), UCLouvain, B-1200 Brussels, Belgium; [email protected] (B.L.); [email protected] (C.B.); [email protected] (M.-C.M.); Department of Plastic and Reconstructive Surgery, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200 Brussels, Belgium 
 Pole of Morphology, Institute of Experimental and Clinical Research (IREC), UCLouvain, B-1200 Brussels, Belgium; [email protected] (B.L.); [email protected] (C.B.); [email protected] (M.-C.M.) 
First page
153
Publication year
2022
Publication date
2022
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2618238978
Copyright
© 2021 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 (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.