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 physiologic or pathologic stimuli. The ubiquitin-proteasome system plays a critical role in the pathogenesis of cardiac hypertrophy. However, as a key component of the ubiquitin-proteasome system, the role of deubiquitinating enzymes in cardiac hypertrophy is not well understood. In this study, we observed that the expression level of deubiquitinase USP47 was increased in hypertrophic hearts and angiotensin II (Ang II)-stimulated neonatal rat cardiomyocytes. 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 prohypertrophic effect of Ang II. Further investigation demonstrated that USP47 inhibited O-GlcNAcylation in cardiomyocytes by controlling the expression of O-GlcNAcase. Mechanistically, USP47 bound, deubiquitinated, and stabilized protein arginine methyltransferase 5 (PRMT5), thus upregulating O-GlcNAcase expression. We found that the restoration of PRMT5 abolished the prohypertrophic 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.