Ubiquitin-specific protease 14 regulates cardiac hypertrophy progression by increasing GSK-3β phosphorylation

Biochem Biophys Res Commun. 2016 Sep 23;478(3):1236-41. doi: 10.1016/j.bbrc.2016.08.100. Epub 2016 Aug 18.


Cardiac hypertrophy, a compensatory response to various stimuli in the heart, independently predicts cardiovascular ailments and related deaths. Increasing evidence indicates ubiquitin-proteasome signaling contributes to cardiac hypertrophy regulation. Here, we identified ubiquitin-specific protease 14 (USP14), a 19S proteasome associated deubiquitinase (DUB), as a novel target for cardiac hypertrophy therapy via inhibition of the GSK-3β pathway. Indeed, USP14 expression was increased in an animal model of abdominal aorta constriction. In an angiotensin II (AngII) induced primary neonatal rat cardiomyocyte hypertrophy model, USP14 expression was increased in a time-dependent manner, and reduced USP14 deubiquitinase activity or USP14 knockdown resulted in lower expression levels of the myocardial hypertrophy specific marker β-MHC, and subsequent decreased GSK-3β phosphorylation. In conclusion, USP14 mediates the development of cardiac hypertrophy by promoting GSK-3β phosphorylation, suggesting that USP14 might represent a novel therapeutic target for cardiac hypertrophy treatment.

Keywords: Cardiac hypertrophy; Deubiquitinase; GSK-3β; USP14.

MeSH terms

  • Animals
  • Animals, Newborn
  • Aorta, Abdominal / diagnostic imaging
  • Aorta, Abdominal / pathology
  • Biomarkers / metabolism
  • Cardiomegaly / diagnostic imaging
  • Cardiomegaly / enzymology*
  • Cardiomegaly / pathology*
  • Constriction, Pathologic
  • Disease Models, Animal
  • Disease Progression*
  • Gene Knockdown Techniques
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Heart Ventricles / pathology
  • Male
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myosin Heavy Chains / metabolism
  • Phosphorylation
  • Rats, Sprague-Dawley
  • Ubiquitin Thiolesterase / metabolism*


  • Biomarkers
  • USP14 protein, rat
  • Glycogen Synthase Kinase 3 beta
  • Ubiquitin Thiolesterase
  • Myosin Heavy Chains