USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes

Pathological cardiac hypertrophy can lead to heart failure and is one of the leading causes of death globally. Understanding the molecular mechanism of pathological cardiac hypertrophy will contribute to the treatment of heart failure. Deubiquitinating enzymes (DUBs) are essential to cardiac pathophysiology by precisely controlling protein function, localization, and degradation.This study set out to investigate the role of a DUB, USP25, in pathological cardiac hypertrophy, reveal its molecular mechanism, and hopefully provide a new therapeutic target for heart failure.We revealed increased protein level of USP25 expression in the cardiomyocytes in response to Ang II stimulation. USP25 deficiency aggravated cardiac hypertrophy and cardiac dysfunction under Ang II and TAC treatment. Mechanistically, LC-MS/MS analysis combined with Co-IP was used to identify SERCA2a, an anti-hypertrophy protein, as an interacting protein of USP25. Also, our data showed that USP25 bound to SERCA2a directly via its USP domain and cysteine at position 178 of USP25 exerts deubiquitination to maintain the stability of the SERCA2a protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining calcium content in cardiomyocytes. Moreover, restoration of USP25 expression via with AAV9 vectors in USP25-/- mice attenuated Ang II-induced cardiac hypertrophy and cardiac dysfunction, whereas SERCA2a myocardial overexpression could offset the effect of USP25. Overall design: We performed RNA sequencing analysis on the heart tissues of three control group mice and three Ang II-induced mice.