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Augmented O-GlcNAcylation exacerbates right ventricular dysfunction and remodeling via enhancement of hypertrophy, mitophagy, and fibrosis in mice exposed to long-term intermittent hypoxia

Hypertension Research volume 46, pages 667–678 (2023)Cite this article

Abstract

Previously, we showed that augmented O-linked N-acetylglucosaminylation (O-GlcNAcylation) mitigates cardiac remodeling in O-GlcNAc transferase-transgenic (Ogt-Tg) mice exposed to acute (2-week) intermittent hypoxia (IH) by suppressing nuclear factor of activated T cells (NFAT) and nuclear factor kappa B (NF-κB) via the O-GlcNAcylation of glycogen synthase kinase 3 beta (GSK-3β) and NF-κB p65. Because this effect is time dependent, we exposed Ogt-Tg mice to IH for 4 weeks (IH4W) in the present study. O-GlcNAcylation was significantly enhanced in Ogt-Tg mice vs. wild-type (WT) mice exposed to normoxia and IH4W. Total O-GlcNAcylation levels were significantly increased in WT and Ogt-Tg mice after IH4W vs. normoxia. After IH4W, Ogt-Tg mice displayed significantly exacerbated signs of cardiac hypertrophy and fibrosis in the right ventricles (RVs) but not the left ventricles (LVs). Echocardiography revealed IH4W-induced right ventricular dysfunction. Phosphorylated GSK-3β levels were increased in Ogt-Tg mice vs. WT mice after IH4W, whereas phosphorylated NF-κB p65 levels were unaffected. Mitophagy, which is associated with cardiac dysfunction, was increased in the RVs of Ogt-Tg mice after IH4W. Furthermore, the levels of phosphorylated dynamin-related protein 1 (p-Drp1) were significantly increased, and the expression of mitofusin-2 (MFN2) was significantly decreased. In human embryonic kidney cells, mitochondrial uncoupler-induced mitochondrial dysfunction was accelerated in Ogt-overexpressing cells. In addition to increasing the levels of phosphorylated Smad2, IH4W promoted cardiac fibrosis in the RVs of Ogt-Tg mice. Thus, augmented O-GlcNAcylation may aggravate IH4W-induced right ventricular dysfunction and remodeling by promoting hypertrophy, mitophagy, and fibrosis via GSK-3β inactivation, an increased p-Drp-1/MFN2 ratio, and Smad2 activation, respectively.

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Acknowledgements

We are grateful to Yudai Yamaguchi, Yuhei Yamanaka, Maki Tamura (research assistants at the Department of Cardiovascular Pharmacotherapy and Toxicology, Faculty of Pharmacy) and Yumiko Okumura (Osaka Medical and Pharmaceutical University) for their expert technical assistance.

Funding

This study was partially supported by Grant-in-Aid for Scientific Research (C) no. 25460397 from the Japan Society for the Promotion of Science (MA) under the Ministry of Education, Science, Culture, Sports and Technology of Japan.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan

    Shunichi Yokoe, Tetsuya Hayashi, Takatoshi Nakagawa & Michio Asahi

  2. Department of Cardiovascular Pharmacotherapy and Toxicology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka, Japan

    Tetsuya Hayashi, Ryuji Kato & Yoshio Ijiri

  3. Department of Cardiovascular Medicine, Faculty of Medicine, Osaka Metropolitan University, Osaka, Japan

    Takehiro Yamaguchi & Minoru Yoshiyama

  4. Department of Pharmacology, Faculty of Medicine, Osaka Metropolitan University, Osaka, Japan

    Yasukatsu Izumi

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  1. Shunichi Yokoe
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Yokoe, S., Hayashi, T., Nakagawa, T. et al. Augmented O-GlcNAcylation exacerbates right ventricular dysfunction and remodeling via enhancement of hypertrophy, mitophagy, and fibrosis in mice exposed to long-term intermittent hypoxia. Hypertens Res 46, 667–678 (2023). https://doi.org/10.1038/s41440-022-01088-8

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