Inflammation leads through PGE/EP3 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 knowl...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-06-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708536 |
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| author | 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 |
| author_facet | 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 |
| author_sort | András D Tóth |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9ded375d72b14d9bb30ce9a16e01de06 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9ded375d72b14d9bb30ce9a16e01de062025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-06-0110711610.15252/emmm.201708536Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytesAndrás D Tóth0Richard Schell1Magdolna Lévay2Christiane Vettel3Philipp Theis4Clemens Haslinger5Felix Alban6Stefanie Werhahn7Lina Frischbier8Jutta Krebs‐Haupenthal9Dominique Thomas10Hermann‐Josef Gröne11Metin Avkiran12Hugo A Katus13Thomas Wieland14Johannes Backs15Department of Molecular Cardiology and Epigenetics, Heidelberg UniversityDepartment of Molecular Cardiology and Epigenetics, Heidelberg UniversityDZHK (German Centre for Cardiovascular Research)DZHK (German Centre for Cardiovascular Research)Department of Molecular Cardiology and Epigenetics, Heidelberg UniversityDepartment of Molecular Cardiology and Epigenetics, Heidelberg UniversityDepartment of Molecular Cardiology and Epigenetics, Heidelberg UniversityDepartment of Molecular Cardiology and Epigenetics, Heidelberg UniversityDepartment of Molecular Cardiology and Epigenetics, Heidelberg UniversityDepartment of Molecular Cardiology and Epigenetics, Heidelberg UniversityInstitute of Clinical Pharmacology, Goethe University FrankfurtDepartment of Cellular and Molecular Pathology, German Cancer Research CenterCardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, The Rayne Institute, St Thomas’ HospitalDepartment of Cardiology, Heidelberg UniversityDZHK (German Centre for Cardiovascular Research)Department of Molecular Cardiology and Epigenetics, Heidelberg UniversityAbstract 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.https://doi.org/10.15252/emmm.201708536histone deacetylase 5myocyte enhancer factor 2p21‐activated kinase 2prostaglandin E2protein kinase D |
| spellingShingle | 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 Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytes EMBO Molecular Medicine histone deacetylase 5 myocyte enhancer factor 2 p21‐activated kinase 2 prostaglandin E2 protein kinase D |
| title | Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytes |
| title_full | Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytes |
| title_fullStr | Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytes |
| title_full_unstemmed | Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytes |
| title_short | Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2‐dependent transcription in cardiac myocytes |
| title_sort | inflammation leads through pge ep3 signaling to hdac5 mef2 dependent transcription in cardiac myocytes |
| topic | histone deacetylase 5 myocyte enhancer factor 2 p21‐activated kinase 2 prostaglandin E2 protein kinase D |
| url | https://doi.org/10.15252/emmm.201708536 |
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