Differential regulation of proteasome function in isoproterenol-induced cardiac hypertrophy

Circ Res. 2010 Oct 29;107(9):1094-101. doi: 10.1161/CIRCRESAHA.110.222364. Epub 2010 Sep 2.


Rationale: Proteasomal degradation is altered in many disease phenotypes including cardiac hypertrophy, a prevalent condition leading to heart failure. Our recent investigations identified heterogeneous subpopulations of proteasome complexes in the heart and implicated multiple mechanisms for their regulation.

Objective: The study aimed at identification of molecular mechanisms changing proteasome function in the hypertrophic heart.

Method and results: Proteasome function, expression, and assembly were analyzed during the development of cardiac hypertrophy induced by β-adrenergic stimulation. The analysis revealed, for the first time, divergent regulation of proteasome function in cardiac hypertrophy. Proteasome complexes have 3 different proteolytic activities, which are ATP-dependent for 26S complexes (19S assembled with 20S) and ATP-independent for 20S core particles. The 26S activities were enhanced in hypertrophic hearts, partially because of increased expression and assembly of 19S subunits with 20S core complexes. In contrast, caspase- and trypsin-like 20S activities were significantly decreased. Activation of endogenous cAMP-dependent protein kinase (PKA) rescued the depressed 20S functions, supporting the notion that PKA signaling is a positive regulator of protein degradation in the heart. Chymotrypsin-like 20S activity was stably maintained during cardiac remodeling, indicating a switch in proteasome subpopulations, which was supported by altered expression and incorporation of inducible β subunits.

Conclusions: Three novel mechanisms for the regulation of proteasome activities were discovered in the development of cardiac hypertrophy: (1) increased incorporation of inducible subunits in 20S proteasomes; (2) enhanced 20S sensitivity to PKA activation; and (3) increased 26S assembly. PKA modulation of proteasome complexes may provide a novel therapeutic avenue for restoration of cardiac function in the diseased myocardium.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / chemically induced*
  • Cardiomegaly / enzymology*
  • Cardiomegaly / pathology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Hydrolysis
  • Isoproterenol / toxicity*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Proteasome Endopeptidase Complex / biosynthesis
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Endopeptidase Complex / physiology*
  • Protein Denaturation / drug effects
  • Protein Denaturation / genetics
  • Protein Processing, Post-Translational / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / genetics


  • Cyclic AMP-Dependent Protein Kinases
  • Proteasome Endopeptidase Complex
  • Isoproterenol