%0 Journal Article
%A Tóth, András D
%A Schell, Richard
%A Lévay, Magdolna
%A Vettel, Christiane
%A Theis, Philipp
%A Haslinger, Clemens
%A Alban, Felix
%A Werhahn, Stefanie
%A Frischbier, Lina
%A Krebs-Haupenthal, Jutta
%A Thomas, Dominique
%A Gröne, Hermann-Josef
%A Avkiran, Metin
%A Katus, Hugo A
%A Wieland, Thomas
%A Backs, Johannes
%T Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes.
%J EMBO molecular medicine
%V 10
%N 7
%@ 1757-4684
%C Weinheim
%I Wiley-VCH
%M DKFZ-2018-01260
%P e8536 -
%D 2018
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29907596
%2 pmc:PMC6034133
%R 10.15252/emmm.201708536
%U https://inrepo02.dkfz.de/record/136822