AUTHOR=Matsuno Mahito , Yokoe Shunichi , Nagatsuka Takehiro , Morihara Hirofumi , Moriwaki Kazumasa , Asahi Michio 

TITLE=O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1122125

DOI=10.3389/fendo.2023.1122125

ISSN=1664-2392

ABSTRACT=<p><italic>O</italic>-GlcNAc transferase (OGT) modulates many functions of proteins <italic>via O</italic>-GlcNAcylation that adds <italic>O</italic>-linked β-<italic>N</italic>-acetylglucosamine (<italic>O</italic>-GlcNAc) to the serine/threonine residues of proteins. However, the role of <italic>O</italic>-GlcNAcylation in cardiac remodeling and function is not fully understood. To examine the effect of <italic>O</italic>-GlcNAcylation on pressure overload-induced cardiac hypertrophy and subsequent heart failure, transverse aortic constriction (TAC) surgery was performed in wild type (WT) and <italic>Ogt</italic> transgenic (<italic>Ogt</italic>-Tg) mice. Four weeks after TAC (TAC4W), the heart function of <italic>Ogt</italic>-Tg mice was significantly lower than that of WT mice (reduced fractional shortening and increased ANP levels). The myocardium of left ventricle (LV) in <italic>Ogt</italic>-Tg mice became much thinner than that in WT mice. Moreover, compared to the heart tissues of WT mice, <italic>O</italic>-GlcNAcylation of GSK-3β at Ser9 was increased and phosphorylation of GSK-3β at Ser9 was reduced in the heart tissues of <italic>Ogt</italic>-Tg mice, resulting in its activation and subsequent inactivation of nuclear factor of activated T cell (NFAT) activity. Finally, the thinned LV wall and reduced cardiac function induced by TAC4W in <italic>Ogt</italic>-Tg mice was reversed by the treatment of a GSK-3β inhibitor, TDZD-8. These results imply that augmented <italic>O</italic>-GlcNAcylation exacerbates pressure overload-induced heart failure due to a lack of compensatory cardiac hypertrophy <italic>via O</italic>-GlcNAcylation of GSK-3β, which deprives the phosphorylation site of GSK-3β to constantly inactivate NFAT activity to prevent cardiac hypertrophy. Our findings may provide a new therapeutic strategy for cardiac hypertrophy and subsequent heart failure.</p>