TY  - JOUR
AU  - Tóth, András D
AU  - Schell, Richard
AU  - Lévay, Magdolna
AU  - Vettel, Christiane
AU  - Theis, Philipp
AU  - Haslinger, Clemens
AU  - Alban, Felix
AU  - Werhahn, Stefanie
AU  - Frischbier, Lina
AU  - Krebs-Haupenthal, Jutta
AU  - Thomas, Dominique
AU  - Gröne, Hermann-Josef
AU  - Avkiran, Metin
AU  - Katus, Hugo A
AU  - Wieland, Thomas
AU  - Backs, Johannes
TI  - Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes.
JO  - EMBO molecular medicine
VL  - 10
IS  - 7
SN  - 1757-4684
CY  - Weinheim
PB  - Wiley-VCH
M1  - DKFZ-2018-01260
SP  - e8536 -
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29907596
C2  - pmc:PMC6034133
DO  - DOI:10.15252/emmm.201708536
UR  - https://inrepo02.dkfz.de/record/136822
ER  -