{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:42:49Z","timestamp":1790779369074,"version":"4.1.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T00:00:00Z","timestamp":1679443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p><jats:italic>O<\/jats:italic>-GlcNAc transferase (OGT) modulates many functions of proteins <jats:italic>via O<\/jats:italic>-GlcNAcylation that adds <jats:italic>O<\/jats:italic>-linked \u03b2-<jats:italic>N<\/jats:italic>-acetylglucosamine (<jats:italic>O<\/jats:italic>-GlcNAc) to the serine\/threonine residues of proteins. However, the role of <jats:italic>O<\/jats:italic>-GlcNAcylation in cardiac remodeling and function is not fully understood. To examine the effect of <jats:italic>O<\/jats:italic>-GlcNAcylation on pressure overload-induced cardiac hypertrophy and subsequent heart failure, transverse aortic constriction (TAC) surgery was performed in wild type (WT) and <jats:italic>Ogt<\/jats:italic> transgenic (<jats:italic>Ogt<\/jats:italic>-Tg) mice. Four weeks after TAC (TAC4W), the heart function of <jats:italic>Ogt<\/jats: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 <jats:italic>Ogt<\/jats:italic>-Tg mice became much thinner than that in WT mice. Moreover, compared to the heart tissues of WT mice, <jats:italic>O<\/jats:italic>-GlcNAcylation of GSK-3\u03b2 at Ser9 was increased and phosphorylation of GSK-3\u03b2 at Ser9 was reduced in the heart tissues of <jats:italic>Ogt<\/jats: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 <jats:italic>Ogt<\/jats:italic>-Tg mice was reversed by the treatment of a GSK-3\u03b2 inhibitor, TDZD-8. These results imply that augmented <jats:italic>O<\/jats:italic>-GlcNAcylation exacerbates pressure overload-induced heart failure due to a lack of compensatory cardiac hypertrophy <jats:italic>via O<\/jats:italic>-GlcNAcylation of GSK-3\u03b2, which deprives the phosphorylation site of GSK-3\u03b2 to constantly inactivate NFAT activity to prevent cardiac hypertrophy. Our findings may provide a new therapeutic strategy for cardiac hypertrophy and subsequent heart failure.<\/jats:p>","DOI":"10.3389\/fendo.2023.1122125","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T05:50:31Z","timestamp":1679464231000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["O-GlcNAcylation-induced GSK-3\u03b2 activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in 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