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O‐GlcNAc signaling regulates cardiac hypertrophy via NFAT activation
Author(s) -
Tarso Fernandes Facundo Heberty,
Eli Brainard Robert,
Jones Steven Paul
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.978.18
Subject(s) - nfat , calcineurin , medicine , endocrinology , muscle hypertrophy , signal transduction , transcription factor , dephosphorylation , chemistry , phosphorylation , pressure overload , microbiology and biotechnology , phosphatase , biology , biochemistry , transplantation , cardiac hypertrophy , gene
Calcineurin regulates the dephosphorylation and nuclear translocation of the cardiac hypertophy transcription factor, Nuclear Factor of Activated T‐cells (NFAT). O‐linked beta‐N‐acetyl glucosamine (O‐GlcNAc) has emerged as a highly dynamic post‐translational modification of serine and threonine residues regulating physiological and stress processes. Here, we show that hypertrophy (via phenylephrine, 100 μM – 6 hours) augmented O‐GlcNAc signaling and, through the use of an NFAT‐luciferase reporter, was associated with NFAT activation in Neonatal Rat Cardiac Myocytes. Adenoviral O‐GlcNAcase overexpression or hexosamine pathway inhibition (i.e. reduction in O‐GlcNAc signaling) reversed hypertrophy‐induced NFAT activation similar to the prototypic calcineurin inhibitor, cyclosporin A. Interestingly, the O‐glycosylating enzyme O‐GlcNAc Transferase augmented O‐GlcNAc levels and activated NFAT, even in the absence of hypertrophic stimulation. Hearts from mice subjected to pressure overload induced hypertrophy (i.e. Transverse Aortic Constriction) exhibited augmented O‐GlcNAc levels and elevated ANP and BNP expression. Taken together, these results demonstrate a critical role of O‐GlcNAc signaling in NFAT activation during hypertrophy and provide evidence that O‐GlcNAc 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 studies of diabetic cardiomyopathy. Financial support: NIH, American Heart Association