Inflammation leads through PGE/EP signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes

András D Tóth; Richard Schell; Magdolna Lévay; Christiane Vettel; Philipp Theis; Clemens Haslinger; Felix Alban; Stefanie Werhahn; Lina Frischbier; Jutta Krebs-Haupenthal; Dominique Thomas; Hermann-Josef Gröne; Metin Avkiran; Hugo A Katus; Thomas Wieland; Johannes Backs

doi:10.15252/emmm.201708536

Inflammation leads through PGE/EP signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes

András D Tóth, Richard Schell, Magdolna Lévay, Christiane Vettel, Philipp Theis, Clemens Haslinger, Felix Alban, Stefanie Werhahn, Lina Frischbier, Jutta Krebs-Haupenthal, Dominique Thomas, Hermann-Josef Gröne, Metin Avkiran, Hugo A Katus, Thomas Wieland, Johannes Backs

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19 Citations (Scopus)

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.

Original language	English
Journal	EMBO Molecular Medicine
Early online date	15 Jun 2018
DOIs	https://doi.org/10.15252/emmm.201708536
Publication status	E-pub ahead of print - 15 Jun 2018

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Tóth, A. D., Schell, R., Lévay, M., Vettel, C., Theis, P., Haslinger, C., Alban, F., Werhahn, S., Frischbier, L., Krebs-Haupenthal, J., Thomas, D., Gröne, H.-J., Avkiran, M., Katus, H. A., Wieland, T., & Backs, J. (2018). Inflammation leads through PGE/EP signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes. EMBO Molecular Medicine. Advance online publication. https://doi.org/10.15252/emmm.201708536

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title = "Inflammation leads through PGE/EP signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes",

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.",

author = "T{\'o}th, {Andr{\'a}s D} and Richard Schell and Magdolna L{\'e}vay and Christiane Vettel and Philipp Theis and Clemens Haslinger and Felix Alban and Stefanie Werhahn and Lina Frischbier and Jutta Krebs-Haupenthal and Dominique Thomas and Hermann-Josef Gr{\"o}ne and Metin Avkiran and Katus, {Hugo A} and Thomas Wieland and Johannes Backs",

note = "{\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2018",

month = jun,

day = "15",

doi = "10.15252/emmm.201708536",

language = "English",

journal = "EMBO Molecular Medicine",

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Tóth, AD, Schell, R, Lévay, M, Vettel, C, Theis, P, Haslinger, C, Alban, F, Werhahn, S, Frischbier, L, Krebs-Haupenthal, J, Thomas, D, Gröne, H-J, Avkiran, M, Katus, HA, Wieland, T & Backs, J 2018, 'Inflammation leads through PGE/EP signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes', EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201708536

TY - JOUR

T1 - Inflammation leads through PGE/EP signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes

AU - Tóth, András D

AU - Schell, Richard

AU - Lévay, Magdolna

AU - Vettel, Christiane

AU - Theis, Philipp

AU - Haslinger, Clemens

AU - Alban, Felix

AU - Werhahn, Stefanie

AU - Frischbier, Lina

AU - Krebs-Haupenthal, Jutta

AU - Thomas, Dominique

AU - Gröne, Hermann-Josef

AU - Avkiran, Metin

AU - Katus, Hugo A

AU - Wieland, Thomas

AU - Backs, Johannes

PY - 2018/6/15

Y1 - 2018/6/15

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.

AB - 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.

U2 - 10.15252/emmm.201708536

DO - 10.15252/emmm.201708536

M3 - Article

C2 - 29907596

SN - 1757-4684

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

ER -

Inflammation leads through PGE/EP signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes

Abstract

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