A related mechanism for USP18 regulating diabetic cardiomyopathy procession: promoting activity of AKT signaling...

Diabetic cardiomyopathy (DCM) is a common cause of heart failure worldwide. The pathological mechanisms underlying DCM are intricate, involving factors such as oxidative stress, inflammation, and mitochondrial dysfunction. USP18 is a deubiquitinating enzyme that mediates the stability of target proteins. In this study, high glucose (HG)-induced AC16 cells and STZ-induced rats were used as in-vitro and in-vivo DCM models to investigate the role of USP18 in DCM and its related mechanisms. We found that HG stimulation led to abnormal production of reactive oxygen species (ROS), accumulation of inflammation, and mitochondrial damage in AC16 cells. However, these pathological lesions were mitigated after USP18 overexpression. For in-vivo studies, the elevated blood sugar, abnormal heart function, and damage to myocardial tissue were observed in DCM rats. Similar to in-vitro experiments, overexpression of USP18 ameliorated these phenotypes. Mechanistically, immunofluorescence confirmed the binding of USP18 and Notch1 and USP18 mediated the stability of Notch1 with the evidence of Western blot. USP18 was able to restore the level of AKT phosphorylation at Ser473 site in HG-induced AC16 cells and DCM rats. In conclusion, our study demonstrated that USP18 alleviated the myocardial damage by promoting the stability of Notch1, thereby activating AKT signaling pathway in cardiac tissue of DCM rats.