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Published on: June 15, 2018

The CRM1 nuclear export receptor controls pathological cardiac gene expression

Brooke C Harrison1, Charles R Roberts, David B Hood

  • 1Myogen Inc., 7575 W. 103rd Ave., Westminister, CO 80021, USA. timothy.mckinsey@myogen.com

Molecular and Cellular Biology
|December 2, 2004
PubMed

Insights

CRM1 facilitates pathological cardiac hypertrophy by exporting the antihypertrophic enzyme HDAC5 from cardiomyocyte nuclei. Blocking this export with CRM1 antagonists represses pathological gene expression and hypertrophy, suggesting therapeutic potential.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Epigenetics

Background:

  • Pathological cardiac remodeling involves myocyte hypertrophy, leading to heart failure.
  • Subcellular distribution of transcriptional regulators controls pathological cardiac hypertrophy.
  • Nuclear export of transcription factors like NFAT and GATA is CRM1-dependent.

Purpose of the Study:

  • To investigate the role of histone deacetylase 5 (HDAC5) nuclear export in pathological cardiac hypertrophy.
  • To determine if CRM1 mediates HDAC5 nuclear export in response to hypertrophic stimuli.
  • To evaluate the therapeutic potential of targeting CRM1-dependent nuclear export.

Main Methods:

  • Studied the subcellular localization of HDAC5 in cardiomyocytes under hypertrophic conditions.
  • Utilized CRM1 antagonists to block nuclear export of HDAC5.
  • Assessed the effects of CRM1 inhibition on pathological gene expression and cardiomyocyte hypertrophy.
  • Compared CRM1's role in pathological vs. non-pathological cardiac gene activation.

Main Results:

  • HDAC5 is exported from the cardiomyocyte nucleus via a CRM1-mediated pathway in response to hypertrophic signals.
  • CRM1 antagonists inhibit agonist-induced HDAC5 nuclear export, repressing pathological gene expression and hypertrophy.
  • CRM1 activity is not required for non-pathological cardiac gene activation by thyroid hormone and IGF-1.

Conclusions:

  • CRM1 selectively promotes pathological cardiac gene expression by enabling the nuclear export of antihypertrophic factors like HDAC5.
  • Targeting CRM1-dependent nuclear export offers a potential therapeutic strategy for heart failure by suppressing maladaptive cardiac remodeling.

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