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Histone deacetylase inhibitors modulate KATP subunit transcription in HL-1 cardiomyocytes through effects on

Naheed Fatima1, Devin C Cohen1, Gauthaman Sukumar1

  • 1Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences Bethesda, MD, USA.

Frontiers in Pharmacology
|September 1, 2015
PubMed

Insights

Histone deacetylase inhibitors (HDIs) increase cardiac SUR2 expression via epigenetic changes. This process requires cellular cholesterol depletion, revealing a link between cholesterol homeostasis and gene regulation.

Area of Science:

  • Cardiology
  • Epigenetics
  • Molecular Biology

Background:

  • Histone deacetylase inhibitors (HDIs) are investigated for various conditions, including cutaneous T-cell lymphoma.
  • HDIs have been linked to electrocardiographic ST segment changes, suggesting effects on cardiac ion channels.
  • ATP-sensitive potassium (KATP) channels are crucial in cardiac function and are regulated by specific subunits.

Purpose of the Study:

  • To investigate the hypothesis that HDIs affect cardiac KATP channel subunit expression.
  • To explore the epigenetic mechanisms underlying HDI-induced changes in KATP channel subunit expression.
  • To determine the role of cellular cholesterol in mediating the effects of HDIs on KATP channel expression.

Main Methods:

  • Treatment of HL-1 cardiomyocytes and MIN6 pancreatic β-cells with HDIs (romidepsin, trichostatin A).
  • Quantitative mRNA expression analysis for SUR1 and SUR2 KATP channel subunits.
  • Chromatin immunoprecipitation to assess histone modifications (H3K9Ac) at the SUR2 promoter.
  • Assessment of cellular cholesterol levels following HDI treatment.

Main Results:

  • HDIs significantly increased SUR2 (Abcc9) mRNA expression (~20-fold) in cardiomyocytes but not SUR1 (Abcc8) or in pancreatic β-cells.
  • Increased H3K9Ac histone mark enrichment was observed at the SUR2 promoter, indicating epigenetic regulation.
  • HDI treatment led to a depletion of cellular cholesterol, which was found to be essential for the observed increase in SUR2 expression.

Conclusions:

  • KATP channel subunit expression in cardiomyocytes is subject to epigenetic regulation.
  • Cellular cholesterol homeostasis plays a critical role in mediating HDI-induced epigenetic regulation of SUR2 expression.
  • These findings suggest a molecular mechanism for the cardiac effects of HDIs and highlight a novel link between cholesterol and epigenetic control.

Keywords:
Abcc8Abcc9SREBPcholesterolepigeneticsromidepsin

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