Regulation of Type I cytokine receptors as a target for pulmonary arterial hypertension treatment? - 09/06/21
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Résumé |
Introduction |
In pulmonary arterial hypertension (PAH), the current therapies do not target pulmonary vascular remodeling (PVR), the main cause of the disease. Type I cytokine receptors (TypeIR) are known to be overexpressed in PAH pulmonary artery smooth muscle cells (PA-SMCs) and involved in PVR.
Aims and objectives |
To assess whether the regulation of TypeIR intracellular trafficking is altered in PAH, leading to TypeIR overexpression and PVR.
Methods |
We studied TypeIR trafficking through the main regulatory proteins ubiquitin-specific protease 8 (USP8) and ring finger protein (RNF) 41. In PAH patients and in controls, we performed in situ immunostaining in lung samples and western blotting in primary cultures of PA-SMCs isolated from human tissues. We transfected human PA-SMCs with siRNA against USP8 and RNF41 in vitro. In two experimental models, the monocrotaline- and chronic hypoxia-induced PAH, we performed hemodynamic measurements followed by in situ immunostaining and western blotting analysis in lung tissues.
Results |
We showed an increased USP8 and decreased RNF41 expression in PAH lungs compared to controls, and a similar shift in USP8/RNF41 ratio at the protein level in PAH PA-SMCs compared to controls (n=10). We modulated USP8/RNF41 ratio with siRNAs and restored TypeIR expression and its signalling (n=5). Consistent with our human in situ and in vitro results, we confirmed the altered USP8/RNF41 ratio in the two in vivo models (n=8 and n=5).
Conclusions |
TypeIR intracellular trafficking regulation is altered in PAH patients compared to controls, due to a shift in USP8/RNF41 ratio. Restoring USP8/RNF41 ratio in PA-SMCs may represent a potential target in PAH.
Le texte complet de cet article est disponible en PDF.Keyword : Circulation
Plan
Vol 38 - N° 6
P. 581 - juin 2021 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.