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

O-GlcNAc transferase (OGT) modulates many functions of proteins via O-GlcNAcylation that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins. However, the role of O-GlcNAcylation in cardiac remodeling and function is not fully understood. To examine the effect...

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Autores principales: Matsuno, Mahito, Yokoe, Shunichi, Nagatsuka, Takehiro, Morihara, Hirofumi, Moriwaki, Kazumasa, Asahi, Michio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10073727/
https://www.ncbi.nlm.nih.gov/pubmed/37033243
http://dx.doi.org/10.3389/fendo.2023.1122125
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author Matsuno, Mahito
Yokoe, Shunichi
Nagatsuka, Takehiro
Morihara, Hirofumi
Moriwaki, Kazumasa
Asahi, Michio
author_facet Matsuno, Mahito
Yokoe, Shunichi
Nagatsuka, Takehiro
Morihara, Hirofumi
Moriwaki, Kazumasa
Asahi, Michio
author_sort Matsuno, Mahito
collection PubMed
description O-GlcNAc transferase (OGT) modulates many functions of proteins via O-GlcNAcylation that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins. However, the role of O-GlcNAcylation in cardiac remodeling and function is not fully understood. To examine the effect of O-GlcNAcylation on pressure overload-induced cardiac hypertrophy and subsequent heart failure, transverse aortic constriction (TAC) surgery was performed in wild type (WT) and Ogt transgenic (Ogt-Tg) mice. Four weeks after TAC (TAC4W), the heart function of Ogt-Tg mice was significantly lower than that of WT mice (reduced fractional shortening and increased ANP levels). The myocardium of left ventricle (LV) in Ogt-Tg mice became much thinner than that in WT mice. Moreover, compared to the heart tissues of WT mice, O-GlcNAcylation of GSK-3β at Ser9 was increased and phosphorylation of GSK-3β at Ser9 was reduced in the heart tissues of Ogt-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 Ogt-Tg mice was reversed by the treatment of a GSK-3β inhibitor, TDZD-8. These results imply that augmented O-GlcNAcylation exacerbates pressure overload-induced heart failure due to a lack of compensatory cardiac hypertrophy via O-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.
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spelling pubmed-100737272023-04-06 O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice Matsuno, Mahito Yokoe, Shunichi Nagatsuka, Takehiro Morihara, Hirofumi Moriwaki, Kazumasa Asahi, Michio Front Endocrinol (Lausanne) Endocrinology O-GlcNAc transferase (OGT) modulates many functions of proteins via O-GlcNAcylation that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins. However, the role of O-GlcNAcylation in cardiac remodeling and function is not fully understood. To examine the effect of O-GlcNAcylation on pressure overload-induced cardiac hypertrophy and subsequent heart failure, transverse aortic constriction (TAC) surgery was performed in wild type (WT) and Ogt transgenic (Ogt-Tg) mice. Four weeks after TAC (TAC4W), the heart function of Ogt-Tg mice was significantly lower than that of WT mice (reduced fractional shortening and increased ANP levels). The myocardium of left ventricle (LV) in Ogt-Tg mice became much thinner than that in WT mice. Moreover, compared to the heart tissues of WT mice, O-GlcNAcylation of GSK-3β at Ser9 was increased and phosphorylation of GSK-3β at Ser9 was reduced in the heart tissues of Ogt-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 Ogt-Tg mice was reversed by the treatment of a GSK-3β inhibitor, TDZD-8. These results imply that augmented O-GlcNAcylation exacerbates pressure overload-induced heart failure due to a lack of compensatory cardiac hypertrophy via O-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. Frontiers Media S.A. 2023-03-22 /pmc/articles/PMC10073727/ /pubmed/37033243 http://dx.doi.org/10.3389/fendo.2023.1122125 Text en Copyright © 2023 Matsuno, Yokoe, Nagatsuka, Morihara, Moriwaki and Asahi https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Matsuno, Mahito
Yokoe, Shunichi
Nagatsuka, Takehiro
Morihara, Hirofumi
Moriwaki, Kazumasa
Asahi, Michio
O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice
title O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice
title_full O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice
title_fullStr O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice
title_full_unstemmed O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice
title_short O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice
title_sort o-glcnacylation-induced gsk-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10073727/
https://www.ncbi.nlm.nih.gov/pubmed/37033243
http://dx.doi.org/10.3389/fendo.2023.1122125
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