Article ; Online: Central role of ubiquitin-specific protease 8 in leptin signaling pathway in pulmonary arterial hypertension.
2023 Volume 43, Issue 1, Page(s) 120–133
Abstract: 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: ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Humans ; Mice ; Cell Proliferation/physiology ; Familial Primary Pulmonary Hypertension ; Hypertension, Pulmonary ; Leptin/metabolism ; Myocytes, Smooth Muscle ; Pulmonary Arterial Hypertension/metabolism ; Pulmonary Artery ; Signal Transduction ; Ubiquitin-Specific Proteases/metabolism ; Vascular Remodeling |
| Chemical Substances | Leptin ; Ubiquitin-Specific Proteases (EC 3.4.19.12) ; Usp8 protein, mouse (EC 3.4.19.12) ; USP8 protein, human (EC 3.4.19.12) |
| Language | English |
| Publishing date | 2023-09-11 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1062522-7 |
| ISSN | 1557-3117 ; 1053-2498 |
| ISSN (online) | 1557-3117 |
| ISSN | 1053-2498 |
| DOI | 10.1016/j.healun.2023.09.003 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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