Inflammation Leads Through PGE/EP3 Signaling to HDAC5/MEF2-dependent Transcription in Cardiac Myocytes

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 E-2 (PGE(2)) strongly activated MEF2. Using pharmacological and protein-based inhibitors, we demonstrated that PGE(2) regulates MEF2 via the EP3 receptor, the beta gamma subunit of G(i/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 PGE(2) 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.