TY  - JOUR
A1  - Tóth, András D.
A1  - Schell, Richard
A1  - Levay, Magdolna
A1  - Vettel, Christiane
A1  - Theis, Philipp
A1  - Haslinger, Clemens
A1  - Alban, Felix
A1  - Werhahn, Stefanie
A1  - Frischbier, Lina
A1  - Krebs-Haupenthal, Jutta
A1  - Thomas, Dominique Jeanette
A1  - Gröne, Hermann-Josef
A1  - Avkiran, Metin
A1  - Katus, Hugo
A1  - Wieland, Thomas
A1  - Backs, Johannes
T1  - Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytes
T2  - EMBO molecular medicine
N2  - 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.
KW  - histone deacetylase 5
KW  - myocyte enhancer factor 2
KW  - p21-activated kinase 2
KW  - prostaglandin E2
KW  - protein kinase D
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46733
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-467339
SN  - 1757-4684
SN  - 1715-4684
SN  - 1757-4676
N1  - © 2018 The Authors. Published under the terms of the CC BY 4.0 license
VL  - 10
IS  - e8536
SP  - 1
EP  - 16
PB  - Wiley-VCH ; EMBO Press
CY  - Weinheim ; Heidelberg
ER  -