Open AccessInflammation leads through PGE / EP 3 signaling to HDAC 5/ MEF 2‐dependent transcription in cardiac myocytes
Author(s) -
Tóth András D,
Schell Richard,
Lévay Magdolna,
Vettel Christiane,
Theis Philipp,
Haslinger Clemens,
Alban Felix,
Werhahn Stefanie,
Frischbier Lina,
KrebsHaupenthal Jutta,
Thomas Dominique,
Gröne HermannJosef,
Avkiran Metin,
Katus Hugo A,
Wieland Thomas,
Backs Johannes
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708536
Subject(s) - german , university hospital , medicine , research centre , epigenetics , library science , biology , history , genetics , computer science , gene , archaeology
The myocyte enhancer factor 2 ( MEF 2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein‐coupled receptors ( GPCR s) have been reported to activate MEF 2, but a comprehensive analysis of GPCR activators that regulate MEF 2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF 2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E 2 ( PGE 2 ) strongly activated MEF 2. Using pharmacological and protein‐based inhibitors, we demonstrated that PGE 2 regulates MEF 2 via the EP 3 receptor, the βγ subunit of G i/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 ( HDAC 5) and thereby de‐repress MEF 2. In vivo , endotoxemia in MEF 2‐reporter mice induced upregulation of PGE 2 and MEF 2 activation. Our findings provide an unexpected new link between inflammation and cardiac remodeling by de‐repression of MEF 2 through HDAC 5 inactivation, which has potential implications for new strategies to treat inflammatory cardiomyopathies.