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

Type 2 diabetes mellitus (T2DM) 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-G1cNAcylation 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-G1cNAc transferase (Ogt-Tg) mice. Two weeks of IH increased O-G1cNAcylation in the heart tissues of both strains of mice, whereas O-G1cNAcylation 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-kappa B were determined. The O-G1cNAcylation of GSK-3 beta, a negative regulator of NFAT, was significantly increased in Ogt-Tg mice, whereas the phosphorylation of GSK-3 beta was reciprocally reduced. The same result was observed for NF-kappa B p65. An in vitro reporter assay showed that the augmentation of O-GlcNAcylation by an O-G1cNAcase inhibitor suppressed NFAT and NF-kappa B promoter activity. These data suggest that augmented O-G1cNAcylation mitigates IH-induced cardiac remodeling by suppressing NFAT and NF-kappa B activities through the O-GlcNAcylation of GSK-3 beta and NF-kappa B p65.