Ubiquitin-specific protease 15 reverses the protective effects of sevoflurane on cerebral ischemia-reperfusion injury in mice by deubiquitinating transforming growth factor-βR1.

Abstract

BACKGROUND: This study is aimed to elucidate the role of ubiquitin-specific proteases (USP) 15 in cerebral ischemia-reperfusion injury (CIRI) under the influence of sevoflurane (Sev). METHODS: Proteins associated with oxidative stress or apoptosis were measured by western blotting. HT22 cell apoptosis was assessed though flow cytometer. The interaction between USP15 and transforming growth factor-βR1 (TGFβR1) was detected by co-immunoprecipitation assay. ELISA was used to evaluate the activity of superoxide dismutase and malondialdehyde. The ubiquitination of TGFβR1 detected by ubiquitination assay. RESULTS: USP15 was highly expressed in HT22 cells and CIRI mice, with expression levels significantly reduced by Sev treatment. The administration of Sev effectively ameliorated CIRI-induced effects, whereas overexpression of USP15 exacerbated infarct volumes, brain edema, oxidative stress, and apoptosis. Furthermore, the loss of USP15 exhibited the opposite results. Mechanistically, Sev decreased USP15 expression, subsequently inhibiting the deubiquitination of TGFβR1. This process ultimately alleviated CIRI-induced oxidative stress and apoptosis. CONCLUSION: This work firstly verified that USP15 abolished the protective roles of Sev in CIRI, indicating that USP15 suppression may enhance applying effects of Sev in patients with CIRI.