Journal Article

Augmented O-GlcNAcylation attenuates intermittent hypoxia-induced cardiac remodeling through the suppression of NFAT and NF-κB activities in mice

Moriwaki, Kazumasa, Yamaguchi, Takehiro, Furukawa, Yuichi, Nomura, Atsuo, Hayashi, Tetsuya, Izumi, Yasukatsu, Kato, Ryuji, Nakagawa, Takatoshi, Yokoe, Shunichi, Asahi, Michio, Yoshiyama, Minoru, Ijiri, Yoshio

2019

Overview

Type 2 diabetes mellitus (T DM) has been reported to be associated with cardiac remodeling. Although O-GlcNAcylation is known to be elevated in diabetic and ischemic hearts, the effects of O-GlcNAcylation on cardiac remodeling induced by intermittent hypoxia (IH), such as sleep apnea syndrome (SAS), remain unknown. To evaluate the effects, we induced IH in wild-type (WT) and transgenic O-GlcNAc transferase (Ogt-Tg) mice. Two weeks of IH increased O-GlcNAcylation in the heart tissues of both strains of mice, whereas O-GlcNAcylation in Ogt-Tg mice was significantly higher than that in WT mice under both normoxic and IH conditions. WT mice exhibited cardiac remodeling after IH, whereas cardiac remodeling was significantly attenuated in Ogt-Tg mice. Oxidative stress and apoptosis increased after IH in both strains of mice, whereas the rate of increase in these processes in Ogt-Tg mice was significantly lower than that in WT mice. To examine the mechanism of cardiac remodeling attenuation in Ogt-Tg mice after IH, the effects of O-GlcNAcylation on the activities of the master regulators nuclear factor of activated T cells (NFAT) and NF-κB were determined. The O-GlcNAcylation of GSK-3β, a negative regulator of NFAT, was significantly increased in Ogt-Tg mice, whereas the phosphorylation of GSK-3β was reciprocally reduced. The same result was observed for NF-κB p65. An in vitro reporter assay showed that the augmentation of O-GlcNAcylation by an O-GlcNAcase inhibitor suppressed NFAT and NF-κB promoter activity. These data suggest that augmented O-GlcNAcylation mitigates IH-induced cardiac remodeling by suppressing NFAT and NF-κB activities through the O-GlcNAcylation of GSK-3β and NF-κB p65.

• Publisher: Nature Publishing Group
• Subject: Acylation / Animals / Cardiovascular system / Cell Line / Diabetes Mellitus, Type 2 - complications / Diabetes Mellitus, Type 2 - pathology / Echocardiography / Glycogen Synthase Kinase 3 beta - metabolism / HEK293 Cells / Humans / Hypertension / Hypoxia / Hypoxia - pathology / Mice / Mice, Transgenic / Myocardium - metabolism / Myocardium - pathology / N-Acetylglucosaminyltransferases - genetics / N-Acetylglucosaminyltransferases - metabolism / NF-kappa B - metabolism / NFATC Transcription Factors - metabolism / Oxidative Stress / Phosphorylation / Rodents / Sleep apnea / Ventricular Remodeling