title: Inhibition of cardiomyocyte hypertrophy by protein arginine methyltransferase 5.
abstract: Protein arginine methyltransferase 5 (PRMT5), a protein arginine methyltransferase that catalyzes the symmetrical dimethylation of arginine residues within target proteins, has been implicated in many essential cellular processes ranging from the regulation of gene expression to cell proliferation and differentiation. PRMT5 is highly expressed in the heart; the functional role of PRMT5 in the heart, however, remains largely elusive. In the present study, we show that PRMT5 specifically interacts with GATA4 in both co-transfected HEK293T cells and neonatal rat cardiomyocytes by co-immunoprecipitation. Importantly, this interaction leads to the arginine methylation of GATA4 at positions of 229, 265, and 317, which leads to an inhibition of the GATA4 transcriptional activity, predominantly through blocking the p300-mediated acetylation of GATA4 in cardiomyocytes. Moreover, overexpression of PRMT5 substantially inhibited the acetylation of GATA4 and cardiac hypertrophic responses in phenylephrine-stimulated cardiomyocytes, whereas knockdown of PRMT5 induced GATA4 activation and cardiomyocyte hypertrophy. Furthermore, in response to phenylephrine stimulation, PRMT5 translocates into the cytoplasm, thus relieving its repression on GATA4 activity in the nucleus and leading to hypertrophic gene expression in cardiomyocytes. These findings indicate that PRMT5 is an essential regulator of myocardial hypertrophic signaling and suggest that strategies aimed at activating PRMT5 in the heart may represent a potential therapeutic approach for the prevention of cardiac hypertrophy and heart failure.
authors.affiliation: From the Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: From the Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Bing
authors.initials: B
authors.lastname: Yi
authors.affiliation: From the Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 jianxin.sun@jefferson.edu.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D001483:Base Sequence; D006332:Cardiomegaly / Q000201:enzymology*; D002460:Cell Line; D050991:GATA4 Transcription Factor / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008745:Methylation; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: Cardiomyocyte; Post-translational Modification (PTM); Protein Arginine N-Methyltransferase 5 (PRMT5); Transcription Factor; Transcription Regulation