Proteasome functional insufficiency in cardiac pathogenesis

Xuejun Wang, Jie Li, Hanqiao Zheng, Huabo Su, Saul R. Powell

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

The ubiquitin-proteasome system (UPS) is responsible for the degradation of most cellular proteins. Alterations in cardiac UPS, including changes in the degradation of regulatory proteins and proteasome functional insufficiency, are observed in many forms of heart disease and have been shown to play an important role in cardiac pathogenesis. In the past several years, remarkable progress in understanding the mechanisms that regulate UPS-mediated protein degradation has been achieved. A transgenic mouse model of benign enhancement of cardiac proteasome proteolytic function has been created. This has led to the first demonstration of the necessity of proteasome functional insufficiency in the genesis of important pathological processes. Cardiomyocyte-restricted enhancement of proteasome proteolytic function by overexpression of proteasome activator 28α protects against cardiac proteinopathy and myocardial ischemia-reperfusion injury. Additionally, exciting advances have recently been achieved in the search for a pharmacological agent to activate the proteasome. These breakthroughs are expected to serve as an impetus to further investigation into the involvement of UPS dysfunction in molecular pathogenesis and to the development of new therapeutic strategies for combating heart disease. Aninterplay between the UPS and macroautophagy is increasingly suggested in noncardiac systems but is not well understood in the cardiac system. Further investigations into the interplay are expected to provide a more comprehensive picture of cardiac protein quality control and degradation.

Original languageEnglish (US)
Pages (from-to)2207-2219
Number of pages13
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume301
Issue number6
DOIs
StatePublished - Dec 2011

Keywords

  • Congestive heart failure
  • Ischemia-reperfusion injury
  • Proteasome activator
  • Proteinopathy
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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