Angiotensin II-induced calcium overload affects mitochondrial functions in cardiac hypertrophy by targeting the USP2/MFN2 axis.

Ubiquitination, a common type of post-translational modification, is known to affect various diseases, including cardiac hypertrophy. Ubiquitin-specific peptidase 2 (USP2) plays a crucial role in regulating cell functions, but its role in cardiac functions remains elusive. The present study aims to investigate the mechanism of USP2 in cardiac hypertrophy. Animal and cell models of cardiac hypertrophy were established using Angiotensin II (Ang II) induction. Our experiments revealed that Ang II induced USP2 downregulation in the in vitro and in vivo models. USP2 overexpression suppressed the degree of cardiac hypertrophy (decreased ANP, BNP, and β-MHC mRNA levels, cell surface area, and ratio of protein/DNA), calcium overload (decreased Ca2+ concentration and t-CaMKⅡ and p-CaMKⅡ, and increased SERCA2), and mitochondrial dysfunction (decreased MDA and ROS and increased MFN1, ATP, MMP, and complex Ⅰ and II) both in vitro and in vivo. Mechanically, USP2 interacted with MFN2 and improved the protein level of MFN2 through deubiquitination. Rescue experiments confirmed that MFN2 downregulation neutralized the protective role of USP2 overexpression in cardiac hypertrophy. Overall, our findings suggested that USP2 overexpression mediated deubiquitination to upregulate MFN2, thus alleviating calcium overload-induced mitochondrial dysfunction and cardiac hypertrophy.