AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation.

Autor:	Gélinas R; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Mailleux F; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Dontaine J; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Bultot L; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Demeulder B; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Ginion A; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Daskalopoulos EP; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Esfahani H; Pole of Pharmacotherapy, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Dubois-Deruy E; Pole of Pharmacotherapy, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Lauzier B; l'institut du thorax, INSERM, CNRS, Univ. Nantes, Nantes, 44007, France., Gauthier C; l'institut du thorax, INSERM, CNRS, Univ. Nantes, Nantes, 44007, France., Olson AK; Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Research Institute, Seattle, 98105-0371, WA, USA.; Montreal Heart Institute, Montreal, H1T 1C8, Canada., Bouchard B; Montreal Heart Institute, Montreal, H1T 1C8, Canada., Des Rosiers C; Montreal Heart Institute, Montreal, H1T 1C8, Canada.; Department of Nutrition, Université de Montréal, Montreal, H3T 1A8, Canada., Viollet B; Institut Cochin, INSERM U1016, 75014, Paris, France.; CNRS UMR8104, 75014, Paris, France.; Université Paris Descartes, Sorbonne Paris Cité, Paris, 75014, France., Sakamoto K; Nestlé Institute of Health Sciences SA, Lausanne, 1015, Switzerland., Balligand JL; Pole of Pharmacotherapy, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Vanoverschelde JL; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium.; Division of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, 1200, Belgium., Beauloye C; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium.; Division of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, 1200, Belgium., Horman S; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium., Bertrand L; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, 1200, Belgium. luc.bertrand@uclouvain.be.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 Jan 25; Vol. 9 (1), pp. 374. Date of Electronic Publication: 2018 Jan 25.
DOI:	10.1038/s41467-017-02795-4
Abstrakt:	AMP-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy. Here, we show that submaximal AMPK activation blocks cardiomyocyte hypertrophy without affecting downstream targets previously suggested to be involved, such as p70 ribosomal S6 protein kinase, calcineurin/nuclear factor of activated T cells (NFAT) and extracellular signal-regulated kinases. Instead, cardiomyocyte hypertrophy is accompanied by increased protein O-GlcNAcylation, which is reversed by AMPK activation. Decreasing O-GlcNAcylation by inhibitors of the glutamine:fructose-6-phosphate aminotransferase (GFAT), blocks cardiomyocyte hypertrophy, mimicking AMPK activation. Conversely, O-GlcNAcylation-inducing agents counteract the anti-hypertrophic effect of AMPK. In vivo, AMPK activation prevents myocardial hypertrophy and the concomitant rise of O-GlcNAcylation in wild-type but not in AMPKα2-deficient mice. Treatment of wild-type mice with O-GlcNAcylation-inducing agents reverses AMPK action. Finally, we demonstrate that AMPK inhibits O-GlcNAcylation by mainly controlling GFAT phosphorylation, thereby reducing O-GlcNAcylation of proteins such as troponin T. We conclude that AMPK activation prevents cardiac hypertrophy predominantly by inhibiting O-GlcNAcylation.
Databáze:	MEDLINE
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