Paper of the Month

June 2018


Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytes. EMBO Molecular Medicine (2018), DZHK authors: Tóth, Schell, Lévay, Vettel, Theis, Haslinger, Alban, Werhahn, Frischbier, Krebs‐Haupenthal, Katus, Wieland, Backs

Different causes lead to heart failure. Therefore, there is an urgent need to identify distinct and common signaling pathways in different forms of heart failure to develop heart failure entity-specific therapies. Since the DZHK has been established, DZHK scientists in Heidelberg/Mannheim are interested in dissecting signaling pathways in different forms of heart failure.

In a collaboration with Mannheim (DZHK PI Thomas Wieland), DZHK professor Johannes Backs and his colleagues (first authors András Tóth and Richard Schell) found now that one specific mediator of pro-inflammatory signaling, prostaglandin E2 (PGE2), signals through EP3 receptors on cardiac myocytes via protein kinase D and a Rac1-dependent pathway to an epigenetic repressor complex partly consisting of histone deacetylase 5 (HDAC5). This signaling pathway leads to de-repression of the myocyte enhancer factor 2 (MEF2), which represents a transcription factor that is crucial for the development of heart failure. Together with the previous findings of the group of Johannes Backs (Lehmann et al. 2018, Nat Med. 24:62-72, paper of the month Dec 2017), showing that MEF2 regulates cardiac function through metabolically-controlled changes in calcium homeostasis, this work points now to a new model how cardiac inflammation may regulate cardiac function through a PGE2-induced epigenetic signaling cascade in cardiac myocytes.

These findings led to the identification of several novel therapeutic targets such as the EP3 receptor, protein kinase D or HDAC5 to potentially treat inflammatory cardiomyopathies including sepsis-induced cardiomyopathies or myocarditis. In the Backs lab, there are currently studies ongoing that aim at providing an in vivo proof of concept that supports this therapeutic strategy towards new anti-inflammatory therapies of heart failure.

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