Department of Molecular Cardiology and Epigenetics, Heidelberg University, Heidelberg, Germany.
DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.
EMBO Mol Med. 2018 Jul;10(7). doi: 10.15252/emmm.201708536.
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 (PGE) strongly activated MEF2. Using pharmacological and protein-based inhibitors, we demonstrated that PGE regulates MEF2 via the EP receptor, the βγ subunit of G 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. , endotoxemia in MEF2-reporter mice induced upregulation of PGE 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.
肌细胞增强因子 2（MEF2）调节心肌细胞中的转录和成年心脏的不良重构。已经报道 G 蛋白偶联受体（GPCR）的激活剂可以激活 MEF2，但是据我们所知，尚未对调节 MEF2 的 GPCR 激活剂进行全面分析。在这里，我们测试了几种 GPCR 激动剂，以检测它们在新生大鼠心室肌细胞中激活 MEF2 报告基因的能力。炎症介质前列腺素 E（PGE）强烈激活 MEF2。使用药理学和基于蛋白质的抑制剂，我们证明 PGE 通过 EP 受体、G 蛋白的βγ亚基和同时激活的两条下游途径来调节 MEF2。第一条途径由 Tiam1、Rac1 和其效应物 p21 激活激酶 2 组成，第二条途径由蛋白激酶 D 组成。这两种途径都集中在组蛋白去乙酰化酶 5（HDAC5）上并使其失活，从而使 MEF2 去抑制。此外，在 MEF2 报告基因小鼠中，内毒素血症诱导 PGE 和 MEF2 激活的上调。我们的研究结果通过 HDAC5 失活使 MEF2 去抑制，为炎症性心肌病的治疗提供了新的策略，为炎症与心脏重构之间提供了一个意想不到的新联系。
