Inflammation leads through PGE/EP 3 signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes

EMBO Mol Med. 2018 Jul;10(7):e8536. doi: 10.15252/emmm.201708536.

Abstract

The myocyte enhancer factor 2 (MEF2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein-coupled receptors (GPCRs) have been reported to activate MEF2, but a comprehensive analysis of GPCR activators that regulate MEF2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E2 (PGE2) strongly activated MEF2. Using pharmacological and protein-based inhibitors, we demonstrated that PGE2 regulates MEF2 via the EP3 receptor, the βγ subunit of Gi/o protein and two concomitantly activated downstream pathways. The first consists of Tiam1, Rac1, and its effector p21-activated kinase 2, the second of protein kinase D. Both pathways converge on and inactivate histone deacetylase 5 (HDAC5) and thereby de-repress MEF2. In vivo, endotoxemia in MEF2-reporter mice induced upregulation of PGE2 and MEF2 activation. Our findings provide an unexpected new link between inflammation and cardiac remodeling by de-repression of MEF2 through HDAC5 inactivation, which has potential implications for new strategies to treat inflammatory cardiomyopathies.

Keywords: histone deacetylase 5; myocyte enhancer factor 2; p21‐activated kinase 2; prostaglandin E2; protein kinase D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dinoprostone / metabolism*
  • Female
  • Histone Deacetylases / metabolism
  • Inflammation / metabolism
  • Inflammation Mediators / metabolism*
  • MEF2 Transcription Factors / metabolism*
  • Male
  • Mice, Inbred BALB C
  • Myocytes, Cardiac / metabolism*
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP3 Subtype / metabolism*
  • Signal Transduction*

Substances

  • Inflammation Mediators
  • MEF2 Transcription Factors
  • Receptors, Prostaglandin E, EP3 Subtype
  • Hdac5 protein, rat
  • Histone Deacetylases
  • Dinoprostone