USP15 promotes proliferation, migration, and apoptosis resistance of pulmonary arterial smooth muscle cells by targeting MDM2.

Pulmonary vascular remodeling is the core pathological feature of pulmonary arterial hypertension (PAH). This process involves intricate changes in pulmonary arterial smooth muscle cells (PASMC), such as proliferation, migration, and resistance to apoptosis. Recent in-depth research has uncovered that ubiquitination or deubiquitination may play a vital role in pulmonary vascular remodeling by regulating the stability of substrate proteins and nuclear localization. The development of drugs targeting ubiquitination or deubiquitination enzymes may offer new strategies for preventing and treating PAH. We initially identified deubiquitinase-related genes that were differentially expressed in the lung tissues of PAH patients using the GEO database. These findings were then validated in two classic PAH rat models induced by MCT or SuHx. Our experimental results revealed a significant increase in the expression of USP15 in both models, particularly in the pulmonary vascular smooth muscle layer. Furthermore, we observed that in our PDGF-BB or hypoxia-induced PASMC model studies, the proliferation, migration, and apoptotic resistance of PASMC induced by PDGF-BB or hypoxia were effectively inhibited by USP15 siRNA. Subsequent mechanism studies demonstrated that silencing USP15 prevented the up-regulation of murine double minute 2 (MDM2) in PASMC induced by PDGF-BB or hypoxia. Conversely, the overexpression of USP15 facilitated proliferation, migration, and apoptosis resistance in PASMC, which was associated with the increased expression of MDM2. USP15 may facilitate the proliferation, migration, and apoptosis resistance of PASMC by targeting MDM2 expression and ultimately participating in pulmonary vascular remodeling. Therefore, the USP15/MDM2 pathway could be a potential therapeutic target for preventing pulmonary vascular remodeling.