The Deficiency of USP20 Alleviates Pressure Overload-Induced Cardiac Hypertrophy via the NF-κB Signaling Pathway.

Ubiquitin-specific protease 20 (USP20) belongs to the ubiquitin-specific protease (USP) family, which represents the largest subfamily of deubiquitinating enzymes. It plays a critical role in regulating cellular signaling transduction, maintaining protein stability, and influencing the development of various diseases. This study revealed that USP20 expression was significantly upregulated in transverse aortic constriction (TAC)-induced hypertrophic hearts and in angiotensin II (AngII)-stimulated neonatal rat cardiomyocytes (NRCMs). This study aims to investigate the potential protective role of USP20 deficiency in pressure overload-induced cardiac hypertrophy and to elucidate the underlying molecular mechanisms. Pathological cardiac hypertrophy was induced in mice via transverse aortic constriction (TAC) surgery. Following the procedure, relevant groups of mice were administered shUSP20 adenovirus via tail vein injection, with the TAC intervention lasting 28 days. The results showed that USP20 significantly exacerbated TAC-induced cardiomyocyte apoptosis and inflammatory responses, while simultaneously impairing cardiac function and aggravating myocardial hypertrophy. In vitro experiments further confirmed that USP20 markedly aggravated angiotensin II (AngII)-induced cardiomyocyte hypertrophy. Moreover, USP20 enhanced inflammatory responses and apoptosis levels in hypertrophic myocardium, as evidenced by increased levels of Bax, TNF-α, IL-6, and IL-1β, along with a decrease in Bcl2. Mechanistically, USP20 elevated the phosphorylation level of P65, and the protective effect of USP20 knockdown against AngII-induced cellular hypertrophy was further enhanced by co-treatment with the NF-κB inhibitor Bay11-7082. USP20 exacerbates cardiac hypertrophy by promoting P65 phosphorylation, which subsequently enhances the release of inflammatory cytokines and apoptotic proteins.