The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation · 2023
Central role of ubiquitin-specific protease 8 in leptin signaling pathway in pulmonary arterial hypertension.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Jutant Etienne-Marie, Chelgham Mustapha K, Ottaviani Mina, Thuillet Raphaël, Le Vely Benjamin, Humbert Marc, Guignabert Christophe, Tu Ly, Huertas Alice
Аннотация
BACKGROUND: Leptin receptor (ObR-b) is overexpressed in pulmonary artery smooth muscle cells (PA-SMCs) from patients with pulmonary arterial hypertension (PAH) and is implicated in both mechanisms that contribute to pulmonary vascular remodeling: hyperproliferation and inflammation. Our aim was to investigate the role of ubiquitin-specific peptidase 8 (USP8) in ObR-b overexpression in PAH.
METHODS: We performed in situ and in vitro experiments in human lung specimens and isolated PA-SMCs combined with 2 different in vivo models in rodents and we generated a mouse with an inducible USP8 deletion specifically in smooth muscles.
RESULTS: Our results showed an upregulation of USP8 in the smooth muscle layer of distal pulmonary arteries from patients with PAH, and upregulation of USP8 expression in PAH PA-SMCs, compared to controls. USP8 inhibition in PAH PA-SMCs significantly blocked both ObR-b protein expression level at the cell surface as well as ObR-b-dependant intracellular signaling pathway as shown by a significant decrease in pSTAT3 expression. USP8 was required for ObR-b activation in PA-SMCs and its inhibition prevented Ob-mediated cell proliferation through STAT3 pathway. USP8 inhibition by the chemical inhibitor DUBs-IN-2 protected against the development of experimental PH in the 2 established experimental models of PH. Targeting USP8 specifically in smooth muscle cells in a transgenic mouse model also protected against the development of experimental PH.
CONCLUSIONS: Our findings highlight the role of USP8 in ObR-b overexpression and pulmonary vascular remodeling in PAH.
METHODS: We performed in situ and in vitro experiments in human lung specimens and isolated PA-SMCs combined with 2 different in vivo models in rodents and we generated a mouse with an inducible USP8 deletion specifically in smooth muscles.
RESULTS: Our results showed an upregulation of USP8 in the smooth muscle layer of distal pulmonary arteries from patients with PAH, and upregulation of USP8 expression in PAH PA-SMCs, compared to controls. USP8 inhibition in PAH PA-SMCs significantly blocked both ObR-b protein expression level at the cell surface as well as ObR-b-dependant intracellular signaling pathway as shown by a significant decrease in pSTAT3 expression. USP8 was required for ObR-b activation in PA-SMCs and its inhibition prevented Ob-mediated cell proliferation through STAT3 pathway. USP8 inhibition by the chemical inhibitor DUBs-IN-2 protected against the development of experimental PH in the 2 established experimental models of PH. Targeting USP8 specifically in smooth muscle cells in a transgenic mouse model also protected against the development of experimental PH.
CONCLUSIONS: Our findings highlight the role of USP8 in ObR-b overexpression and pulmonary vascular remodeling in PAH.
Предметные рубрики MeSH
AnimalsHumansMiceCell ProliferationFamilial Primary Pulmonary HypertensionHypertension, PulmonaryLeptinMyocytes, Smooth MusclePulmonary Arterial HypertensionPulmonary ArterySignal TransductionUbiquitin-Specific ProteasesVascular RemodelingEndopeptidasesUbiquitin ThiolesteraseEndosomal Sorting Complexes Required for Transport