Proteasome functional insufficiency activates the calcineurin-NFAT pathway in cardiomyocytes and promotes maladaptive remodelling of stressed mouse hearts

Mingxin Tang, Jie Li, Wei Huang, Huabo Su, Qiangrong Liang, Zongwen Tian, Kathleen M. Horak, Jeffery D. Molkentin, Xuejun Wang

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

AimsProteasome functional insufficiency (PFI) may play an important role in the progression of congestive heart failure but the underlying molecular mechanism is poorly understood. Calcineurin and nuclear factor of activated T-cells (NFAT) are degraded by the proteasome, and the calcineurin-NFAT pathway mediates cardiac remodelling. The present study examined the hypothesis that PFI activates the calcineurin-NFAT pathway and promotes maladaptive remodelling of the heart.Methods and resultsUsing a reporter gene assay, we found that pharmacological inhibition of 20S proteasomes stimulated NFAT transactivation in both mouse hearts and cultured adult mouse cardiomyocytes. Proteasome inhibition stimulated NFAT nuclear translocation in a calcineurin-dependent manner and led to a maladaptive cell shape change in cultured neonatal rat ventricular myocytes. Proteasome inhibition facilitated left ventricular dilatation and functional decompensation and increased fatality in mice with aortic constriction while causing cardiac hypertrophy in the sham surgery group. It was further revealed that both calcineurin protein levels and NFAT transactivation were markedly increased in the mouse hearts with desmin-related cardiomyopathy and severe PFI. Expression of an aggregation-prone mutant desmin also directly increased calcineurin protein levels in cultured cardiomyocytes.ConclusionsThe calcineurin-NFAT pathway in the heart can be activated by proteasome inhibition and is activated in the heart of a mouse model of desmin-related cardiomyopathy that is characterized by severe PFI. The interplay between PFI and the calcineurin-NFAT pathway may contribute to the pathological remodelling of cardiomyocytes characteristic of congestive heart failure.

Original languageEnglish (US)
Pages (from-to)424-433
Number of pages10
JournalCardiovascular research
Volume88
Issue number3
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

Keywords

  • Calcineurin
  • Cardiac remodelling
  • Desmin-related cardiomyopathy
  • Nuclear factors of activated T-cells
  • Proteasome

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Proteasome functional insufficiency activates the calcineurin-NFAT pathway in cardiomyocytes and promotes maladaptive remodelling of stressed mouse hearts'. Together they form a unique fingerprint.

  • Cite this