USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Pathological cardiac hypertrophy is a major cause of heart failure and global mortality.
• Deubiquitinating enzymes (DUBs) are critical regulators of cardiac pathophysiology.
• USP25's role in cardiac hypertrophy remained largely uncharacterized.

Purpose of the Study:

• To investigate the role and molecular mechanism of USP25 in pathological cardiac hypertrophy.
• To elucidate the interaction between USP25 and SERCA2a in cardiac hypertrophy.
• To determine USP25's therapeutic potential in heart failure.

Main Methods:

• Evaluation of USP25 in murine cardiomyocytes and human heart failure tissues.
• Identification of SERCA2a as a USP25 interacting protein using LC-MS/MS and Co-IP.
• Construction of USP25 mutants and adeno-associated virus (AAV) mediated overexpression in vivo.

Main Results:

• USP25 levels were increased in hypertrophic cardiomyocytes and heart failure tissues.
• USP25 deficiency exacerbated cardiac hypertrophy and dysfunction.
• USP25 directly deubiquitinates and stabilizes SERCA2a, preventing its proteasomal degradation and maintaining calcium handling.
• AAV-mediated USP25 restoration attenuated cardiac hypertrophy in mice.

Conclusions:

• USP25 acts as a crucial inhibitor of pathological cardiac hypertrophy.
• USP25 stabilizes SERCA2a through deubiquitination, preserving cardiac function.
• USP25 represents a potential therapeutic target for heart failure treatment.