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Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes

András D Tóth1,2,3, Richard Schell1,2,4, Magdolna Lévay2,5

  • 1Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.

EMBO Molecular Medicine
|June 17, 2018
PubMed

Insights

Inflammation activates cardiac myocyte enhancer factor 2 (MEF2) via prostaglandin E2 (PGE2) and EP3 receptors. This pathway involves G protein signaling, leading to histone deacetylase 5 (HDAC5) inactivation and MEF2 de-repression, impacting cardiac remodeling.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Inflammation Research

Background:

  • Myocyte enhancer factor 2 (MEF2) is crucial for cardiac myocyte transcription and adverse cardiac remodeling.
  • G protein-coupled receptor (GPCR) activators are known to influence MEF2 activity, but a systematic analysis is lacking.

Purpose of the Study:

  • To comprehensively analyze GPCR agonists that regulate MEF2 activity.
  • To elucidate the signaling pathways linking GPCR activation to MEF2 in cardiac myocytes.

Main Methods:

  • Utilized neonatal rat ventricular myocytes with a MEF2 reporter assay.
  • Employed pharmacological and protein-based inhibitors to dissect signaling cascades.
  • Investigated endotoxemia in MEF2-reporter mice to assess in vivo relevance.

Main Results:

  • Prostaglandin E2 (PGE2) strongly activated MEF2.
  • PGE2-induced MEF2 activation occurred via the EP3 receptor and G(i/o) protein.
  • Two downstream pathways, involving Tiam1/Rac1/PAK2 and Protein Kinase D, converged to inactivate Histone Deacetylase 5 (HDAC5), de-repressing MEF2.
  • Endotoxemia in vivo upregulated PGE2 and activated MEF2.

Conclusions:

  • PGE2, through EP3 receptor and specific downstream signaling, inactivates HDAC5 to de-repress MEF2 in cardiac myocytes.
  • This study reveals an unexpected link between inflammation and cardiac remodeling via MEF2 regulation.
  • Findings suggest potential therapeutic strategies for inflammatory cardiomyopathies targeting this pathway.
Keywords:
histone deacetylase 5myocyte enhancer factor 2p21‐activated kinase 2prostaglandin E2protein kinase D

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