Deubiquitinase USP47 ameliorates cardiac hypertrophy through reducing protein O-GlcNAcylation.

Abstract

Cardiac hypertrophy is a crucial risk factor for heart failure when the heart is confronted with physiological or pathological stimuli. The ubiquitin-proteasome system (UPS) plays a critical role in the pathogenesis of cardiac hypertrophy. However, as a key component of the UPS, the role of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is not well understood. Here, we observed that the expression level of deubiquitinase USP47 was increased in hypertrophic hearts and angiotensin II (Ang II)-stimulated neonatal rat cardiomyocytes (NRCMs). Adenovirus-mediated gain- and loss-of-function approaches indicated that USP47 overexpression significantly attenuated Ang II-induced cardiac hypertrophy in vitro and in vivo, whereas endogenous USP47 deficiency promoted the pro-hypertrophic effect of Ang II. Further investigation demonstrated that USP47 inhibited O-GlcNAcylation in cardiomyocytes by controlling the expression of O-GlcNAcase (OGA). Mechanistically, USP47 bound, deubiquitinated, and stabilized protein arginine methyltransferase 5 (PRMT5), thus upregulating OGA expression. We found that the restoration of PRMT5 abolished the pro-hypertrophic effects of USP47 silence in vitro. Therefore, our results provide the first evidence of the involvement of USP47 in cardiac hypertrophy and identify USP47 as a potential target for hypertrophic therapy.