Differential regulation of proteasome function in isoproterenol-induced cardiac hypertrophy

Oliver Drews, Osamu Tsukamoto, David Liem, John Streicher, Yibin Wang, Peipei Ping

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1094-1101
Number of pages8
JournalCirculation research
Volume107
Issue number9
DOIs
StatePublished - Oct 29 2010
Externally publishedYes

Keywords

  • cellular homeostasis
  • heart disease
  • protein degradation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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