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000136822 041__ $$aeng
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000136822 1001_ $$00000-0003-2746-9370$$aTóth, András D$$b0
000136822 245__ $$aInflammation leads through PGE/EP3 signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes.
000136822 260__ $$aWeinheim$$bWiley-VCH$$c2018
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000136822 520__ $$aThe myocyte enhancer factor 2 (MEF2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein-coupled receptors (GPCRs) have been reported to activate MEF2, but a comprehensive analysis of GPCR activators that regulate MEF2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E2 (PGE2) strongly activated MEF2. Using pharmacological and protein-based inhibitors, we demonstrated that PGE2 regulates MEF2 via the EP3 receptor, the βγ subunit of Gi/o protein and two concomitantly activated downstream pathways. The first consists of Tiam1, Rac1, and its effector p21-activated kinase 2, the second of protein kinase D. Both pathways converge on and inactivate histone deacetylase 5 (HDAC5) and thereby de-repress MEF2. In vivo, endotoxemia in MEF2-reporter mice induced upregulation of PGE2 and MEF2 activation. Our findings provide an unexpected new link between inflammation and cardiac remodeling by de-repression of MEF2 through HDAC5 inactivation, which has potential implications for new strategies to treat inflammatory cardiomyopathies.
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000136822 7001_ $$aSchell, Richard$$b1
000136822 7001_ $$aLévay, Magdolna$$b2
000136822 7001_ $$aVettel, Christiane$$b3
000136822 7001_ $$aTheis, Philipp$$b4
000136822 7001_ $$aHaslinger, Clemens$$b5
000136822 7001_ $$aAlban, Felix$$b6
000136822 7001_ $$aWerhahn, Stefanie$$b7
000136822 7001_ $$aFrischbier, Lina$$b8
000136822 7001_ $$aKrebs-Haupenthal, Jutta$$b9
000136822 7001_ $$aThomas, Dominique$$b10
000136822 7001_ $$0P:(DE-He78)00a2ea610aee4a8fca32908fc3d02e91$$aGröne, Hermann-Josef$$b11$$udkfz
000136822 7001_ $$aAvkiran, Metin$$b12
000136822 7001_ $$aKatus, Hugo A$$b13
000136822 7001_ $$aWieland, Thomas$$b14
000136822 7001_ $$00000-0002-2322-2699$$aBacks, Johannes$$b15
000136822 773__ $$0PERI:(DE-600)2485479-7$$a10.15252/emmm.201708536$$gVol. 10, no. 7, p. e8536 -$$n7$$pe8536 -$$tEMBO molecular medicine$$v10$$x1757-4684$$y2018
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000136822 9141_ $$y2018
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