USP38 stabilizes NOX4 and activates CaMKII to enhance ventricular arrhythmias susceptibility in CKD mice

Background: Chronic kidney disease (CKD), with sudden cardiac death (SCD) constituting a primary cause of death, the molecular mechanisms of which are yet to be fully elucidated. Ubiquitin-Specific Protease 38 (USP38) has been implicated in the development and progression of cardiovascular diseases. However, its role in CKD-related ventricular arrhythmias (VAs) is yet to be clarified. This research systematically explores the involvement of USP38 in the development of VAs in CKD.

Methods: This study employed cardiac-specific Usp38 knockout and transgenic Usp38 mice, along with H9c2 cells transduced with adenoviral vectors carrying Usp38 (AdUsp38) or shRNA targeting Usp38 (AdshUsp38). The mouse model was generated via 5/6 nephrectomy, and CKD cell models were created using indoxyl sulfate (IS) induction. These models underwent extensive evaluation, including echocardiography, electrophysiology, histological studies, and molecular analysis.

Results: In CKD mouse models, USP38 expression was markedly elevated and predominantly localized in ventricular myocytes. Knocking out Usp38 markedly decreased the susceptibility and duration of rapid VAs in CKD mice and corrected the abnormal expression of ion channel proteins. Comparable findings were observed in Usp38 transgenic mouse models. From a mechanistic perspective, Usp38 knockout reduced oxidative stress in cardiac tissues and upregulated antioxidative enzyme expression. The enhancement was mainly achieved by increasing NADPH Oxidase 4 (NOX4) ubiquitination and degradation, along with inhibition of downstream CaMKII activity. In contrast, USP38 overexpression had harmful effects on the heart, which were alleviated by NOX4 inhibition.

Conclusion: This study demonstrated that USP38 stabilizes NOX4 expression via deubiquitination, resulting in increased oxidative stress and hyperphosphorylation of CaMKII, which markedly enhances the susceptibility of CKD mice to VAs. These findings underscore the critical regulatory role of USP38 in CKD-related arrhythmias, providing a promising therapeutic target for USP38-directed treatments.

Chronic kidney disease; NADPH oxidase 4; Oxidative stress; USP38; Ventricular arrhythmias.