Ubiquitin‐specific protease 19 blunts pathological cardiac hypertrophy via inhibition of the TAK1‐dependent pathway

Abstract

Ubiquitin‐specific protease 19 (USP19) belongs to USP family and is involved in promoting skeletal muscle atrophy. Although USP19 is expressed in the heart, the role of USP19 in the heart disease remains unknown. The present study provides in vivo and in vitro data to reveal the role of USP19 in preventing pathological cardiac hypertrophy. We generated USP19‐knockout mice and isolated neonatal rat cardiomyocytes (NRCMs) that overexpressed or were deficient in USP19 to investigate the effect of USP19 on transverse aortic constriction (TAC) or phenylephrine (PE)‐mediated cardiac hypertrophy. Echocardiography, pathological and molecular analysis were used to determine the extent of cardiac hypertrophy, fibrosis, dysfunction and inflammation. USP19 expression was markedly increased in rodent hypertrophic heart or cardiomyocytes underwent TAC or PE culturing, the increase was mediated by the reduction of Seven In Absentia Homolog‐2. The extent of TAC‐induced cardiac hypertrophy, fibrosis, dysfunction and inflammation in USP19‐knockout mice was exacerbated. Consistently, gain‐of‐function and loss‐of‐function approaches that involved USP19 in cardiomyocytes suggested that the down‐regulation of USP19 promoted the hypertrophic phenotype, while the up‐regulation of USP19 improved the worsened phenotype. Mechanistically, the USP19‐elicited cardiac hypertrophy improvement was attributed to the abrogation of the transforming growth factor beta‐activated kinase 1 (TAK1)‐p38/JNK1/2 transduction. Furthermore, the inhibition of TAK1 abolished the aggravated hypertrophy induced by the loss of USP19. In conclusion, the present study revealed that USP19 and the downstream of TAK1‐p38/JNK1/2 signalling pathway might be a potential target to attenuate pathological cardiac hypertrophy.

The Protective Effect of Cyanidin‐3‐Glucoside on Myocardial Ischemia‐Reperfusion Injury through Ferroptosis

“…Mounting evidence indicated that USP19 drives numerous cellular process. An important role for USP19 in the innate immune response has now been reported [ 22 ], with USP19 blunting pathological cardiac hypertrophy by inhibiting the inflammatory response [ 23 ]. Increasing literature indicated the correlation between USP family and autophagy.…”

USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes

“…Elucidating the regulatory mechanism of DUBs in cardiac hypertrophy has the promise to provide a new therapeutic strategy. Previous research has already confirmed that the protein levels of USP10 (ubiquitin-specific peptidase 10), 21 USP18, 22 and USP19 23 were increased in mouse cardiac hypertrophy model induced by various factors, while USP2 24 and USP4 6 were consistently decreased in mouse hypertrophic hearts. These DUBs inhibit cardiac hypertrophy, reduce fibrosis levels, and improve cardiac function.…”

Activation of the membrane-bound Nrf1 transcription factor by USP19, a ubiquitin-specific protease C-terminally anchored in the endoplasmic reticulum

“…Thus, USP19 is involved in regulation of cell cycle progression, DNA damage repair, apoptosis and autophagy (Lei et al, 2019;Miao et al, 2020). Here, we found that USP19 interacts with Nrf1 to enhance this CNC-bZIP stability and its transcriptional activity.…”