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.

• Authors: Rujia Miao, Yao Lu, Xue He, Xuelian Liu, Zhiheng Chen, Jiangang Wang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 24 Issue 18 Pg. 10946-10957 (09 2020) ISSN: 1582-4934 [Electronic] England
• PMID: 32798288 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Recombinant Proteins
• Angiotensin II
• Phenylephrine
• Siah2 protein, mouse
• Ubiquitin-Protein Ligases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• Endopeptidases
• USP19 protein, mouse

Topics

• Angiotensin II (toxicity)
• Animals
• Animals, Newborn
• Aortic Valve Stenosis
• CRISPR-Cas Systems
• Cardiomegaly (chemically induced, diagnostic imaging, physiopathology)
• Disease Models, Animal
• Endopeptidases (biosynthesis, deficiency, genetics, physiology)
• Fibrosis
• Inflammation
• MAP Kinase Kinase Kinases (physiology)
• MAP Kinase Signaling System (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Phenylephrine (pharmacology)
• Pressure
• Rats
• Rats, Sprague-Dawley
• Recombinant Proteins (metabolism)
• Ubiquitin-Protein Ligases (physiology)
• Ventricular Remodeling (physiology)