miR-199a Downregulation as a Driver of the NOX4/HIF-1α/VEGF-A Pathway in Thyroid and Orbital Adipose Tissues from Graves' Patients.
Julie CrapsVirginie JorisLelio BaldeschiChantal DaumerieAlessandra CamboniAntoine BuemiBenoit LengeléCatherine BehetsAntonella BoschiMichel MouradMarie-Christine ManyChantal DessyPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- cell proliferation
- endothelial cells
- end stage renal disease
- vascular endothelial growth factor
- signaling pathway
- oxidative stress
- ejection fraction
- transcription factor
- newly diagnosed
- poor prognosis
- peritoneal dialysis
- long noncoding rna
- reactive oxygen species
- prognostic factors
- pi k akt
- type diabetes
- gene expression
- south africa
- ischemia reperfusion injury
- high resolution
- dna damage
- skeletal muscle
- patient reported outcomes
- dna binding
- high throughput
- patient reported
- single molecule