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@ARTICLE{Tth:136822,
      author       = {A. D. Tóth and R. Schell and M. Lévay and C. Vettel and
                      P. Theis and C. Haslinger and F. Alban and S. Werhahn and L.
                      Frischbier and J. Krebs-Haupenthal and D. Thomas and H.-J.
                      Gröne$^*$ and M. Avkiran and H. A. Katus and T. Wieland and
                      J. Backs},
      title        = {{I}nflammation leads through {PGE}/{EP}3 signaling to
                      {HDAC}5/{MEF}2-dependent transcription in cardiac myocytes.},
      journal      = {EMBO molecular medicine},
      volume       = {10},
      number       = {7},
      issn         = {1757-4684},
      address      = {Weinheim},
      publisher    = {Wiley-VCH},
      reportid     = {DKFZ-2018-01260},
      pages        = {e8536 -},
      year         = {2018},
      abstract     = {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.},
      cin          = {G130},
      ddc          = {610},
      cid          = {I:(DE-He78)G130-20160331},
      pnm          = {322 - Genetics and Pathophysiology (POF3-322)},
      pid          = {G:(DE-HGF)POF3-322},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29907596},
      pmc          = {pmc:PMC6034133},
      doi          = {10.15252/emmm.201708536},
      url          = {https://inrepo02.dkfz.de/record/136822},
}