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Histone deacetylase-3 activation promotes tumor necrosis factor-alpha (TNF-alpha) expression in cardiomyocytes during

Huaqing Zhu1, Limei Shan2, Peter W Schiller3

  • 1Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada; Departments of Medicine, London, Ontario N6A 4G5, Canada; Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei 230032, China.

The Journal of Biological Chemistry
|January 26, 2010
PubMed

Insights

Lipopolysaccharides (LPS) trigger tumor necrosis factor-alpha (TNF-alpha) in heart cells. Inhibiting histone deacetylase (HDAC) reduces this response, revealing a new pathway involving mitochondrial reactive oxygen species and c-Src signaling.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Cellular Signaling

Background:

  • Lipopolysaccharides (LPS) are key triggers of sepsis, leading to myocardial depression.
  • Tumor necrosis factor-alpha (TNF-alpha) production in cardiomyocytes contributes to this cardiac dysfunction.
  • The precise molecular mechanisms underlying LPS-induced TNF-alpha expression in cardiomyocytes are not fully elucidated.

Purpose of the Study:

  • To investigate the role of histone deacetylase (HDAC) in regulating TNF-alpha expression in cardiomyocytes.
  • To identify the specific signaling pathways involved in LPS-induced HDAC activation.

Main Methods:

  • Utilized cardiomyocytes to study LPS-induced TNF-alpha production.
  • Assessed HDAC activity and the effect of HDAC inhibition on TNF-alpha expression.
  • Employed NF-kappaB/p65 translocation assays and identified specific HDAC isoforms.
  • Investigated the involvement of mitochondrial reactive oxygen species (ROS) and c-Src signaling.

Main Results:

  • LPS significantly increased HDAC activity in cardiomyocytes.
  • HDAC inhibition reduced LPS-stimulated TNF-alpha expression by preventing NF-kappaB/p65 accumulation at the TNF-alpha promoter.
  • HDAC3 was identified as a key regulator of TNF-alpha production.
  • LPS-induced HDAC activation was found to be mediated by mitochondrial ROS and c-Src signaling.

Conclusions:

  • This study reveals a novel signaling pathway for LPS-induced TNF-alpha expression in cardiomyocytes.
  • The pathway involves mitochondrial ROS, c-Src, and specifically HDAC3.
  • Targeting this pathway could offer new therapeutic strategies for sepsis-induced myocardial depression.

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