title: O-GlcNAc signaling is essential for NFAT-mediated transcriptional reprogramming during cardiomyocyte hypertrophy.
abstract: The regulation of cardiomyocyte hypertrophy is a complex interplay among many known and unknown processes. One specific pathway involves the phosphatase calcineurin, which regulates nuclear translocation of the essential cardiac hypertrophy transcription factor, nuclear factor of activated T-cells (NFAT). Although metabolic dysregulation is frequently described during cardiac hypertrophy, limited insights exist regarding various accessory pathways. One metabolically derived signal, beta-O-linked N-acetylglucosamine (O-GlcNAc), has emerged as a highly dynamic posttranslational modification of serine and threonine residues regulating physiological and stress processes. Given the metabolic dysregulation during hypertrophy, we hypothesized that NFAT activation is dependent on O-GlcNAc signaling. Pressure overload-induced hypertrophy (via transverse aortic constriction) in mice or treatment of neonatal rat cardiac myocytes with phenylephrine significantly enhanced global O-GlcNAc signaling. NFAT-luciferase reporter activity revealed O-GlcNAc-dependent NFAT activation during hypertrophy. Reversal of enhanced O-GlcNAc signaling blunted cardiomyocyte NFAT-induced changes during hypertrophy. Taken together, these results demonstrate a critical role of O-GlcNAc signaling in NFAT activation during hypertrophy and provide evidence that O-GlcNAc signaling is coordinated with the onset and progression of cardiac hypertrophy. This represents a potentially significant and novel mechanism of cardiac hypertrophy, which may be of particular interest in future in vivo studies of hypertrophy.
authors.affiliation: Department of Medicine, Institute of Molecular Cardiology, Louisville, KY 40202, USA.
authors.forename: Heberty T
authors.initials: HT
authors.lastname: Facundo
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brainard
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Watson
authors.forename: Gladys A
authors.initials: GA
authors.lastname: Ngoh
authors.forename: Tariq
authors.initials: T
authors.lastname: Hamid
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
authors.forename: Steven P
authors.initials: SP
authors.lastname: Jones
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D050778:NFATC Transcription Factors; D010656:Phenylephrine; D000117:Acetylglucosamine