Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytes

  • 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.
Author:András D. Tóth, Richard Schell, Magdolna Levay, Christiane Vettel, Philipp Theis, Clemens Haslinger, Felix Alban, Stefanie Werhahn, Lina Frischbier, Jutta Krebs-Haupenthal, Dominique Jeanette ThomasORCiDGND, Hermann-Josef Gröne, Metin Avkiran, Hugo Katus, Thomas WielandORCiDGND, Johannes Backs
Pubmed Id:
Parent Title (English):EMBO molecular medicine
Publisher:Wiley-VCH ; EMBO Press
Place of publication:Weinheim ; Heidelberg
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/06/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/06/19
Tag:histone deacetylase 5; myocyte enhancer factor 2; p21-activated kinase 2; prostaglandin E2; protein kinase D
Page Number:16
First Page:1
Last Page:16
© 2018 The Authors. Published under the terms of the CC BY 4.0 license
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0