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Calcium channel blockers act through nuclear factor Y to control transcription of key cardiac genes

Hyunjoo Cha-Molstad1, Guanlan Xu, Junqin Chen

  • 1Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.

Molecular Pharmacology
|June 27, 2012
PubMed

Insights

Verapamil, a calcium channel blocker, unexpectedly regulates cardiac gene transcription by inhibiting calcineurin signaling, which affects nuclear factor Y (NFY) activity. This pathway influences cardiac apoptosis and gene expression in novel ways.

Area of Science:

  • Cardiovascular Pharmacology
  • Molecular Cardiology
  • Transcriptional Regulation

Background:

  • First-generation calcium channel blockers, like verapamil, are established antihypertensive drugs targeting L-type calcium channels.
  • Emerging evidence suggests verapamil may possess unappreciated transcriptional effects, including the reduction of cardiac proapoptotic thioredoxin-interacting protein (TXNIP) expression.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying verapamil-induced transcriptional repression of TXNIP in the heart.
  • To identify the specific transcription factors and signaling pathways involved in verapamil's cardiac transcriptional effects.

Main Methods:

  • Utilized TXNIP promoter deletion and mutation studies to identify key regulatory elements.
  • Employed overexpression/knockdown, luciferase assays, and chromatin immunoprecipitation (ChIP) assays to identify and validate nuclear factor Y (NFY) as the responsible transcription factor.
  • Investigated the role of calcineurin signaling and histone modifications (H4 deacetylation) in mediating the observed transcriptional changes in cardiomyocytes and in vivo in diabetic mice.

Main Results:

  • A CCAAT element in the TXNIP promoter was identified as crucial for verapamil-induced transcriptional repression.
  • Nuclear factor Y (NFY) was confirmed as the transcription factor mediating this repression.
  • Increased NFY-DNA binding correlated with histone H4 deacetylation and transcriptional repression, driven by calcineurin signaling inhibition.

Conclusions:

  • Verapamil activates a novel calcineurin-NFY signaling cascade in the heart, impacting cardiac gene transcription and apoptosis.
  • This pathway's influence extends beyond TXNIP, suggesting broader modulation of NFY target genes.
  • Verapamil's effects on cardiac biology may involve previously unrecognized transcriptional regulatory mechanisms.

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