Regulation of Type I cytokine receptors as a target for pulmonary arterial hypertension treatment? - 09/06/21
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.
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.
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).
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
Vol 38 - N° 6P. 581 - juin 2021 Retour au numéro
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