Augmented O-GlcNAcylation attenuates intermittent hypoxia-induced cardiac remodeling through the suppression of NFAT and NF-κB activities in mice
Augmented O-GlcNAcylation attenuates intermittent hypoxia-induced cardiac remodeling through the suppression of NFAT and NF-κB activities in mice
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增强的 O-GlcNAc 酰化通过抑制小鼠 NFAT 和 NF-κB 活性来减轻间歇性缺氧诱导的心脏重塑
DOI：
10.1038/s41440-019-0311-x
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发表时间：
2019
影响因子：
5.4
通讯作者：
Asahi Michio
中科院分区：
文献类型：
--
作者：
Nakagawa Takatoshi;Furukawa Yuichi;Hayashi Tetsuya;Nomura Atsuo;Yokoe Shunichi;Moriwaki Kazumasa;Kato Ryuji;Ijiri Yoshio;Yamaguchi Takehiro;Izumi Yasukatsu;Yoshiyama Minoru;Asahi Michio
据报道，2 型糖尿病 (T2DM) 与心脏重塑有关。尽管已知O-GlcNA酰化在糖尿病和缺血性心脏中升高，但O-GlcNA酰化对间歇性缺氧(IH)如睡眠呼吸暂停综合征(SAS)引起的心脏重塑的影响仍不清楚。为了评估效果，我们在野生型 (WT) 和转基因 O-GlcNAc 转移酶 (Ogt-Tg) 小鼠中诱导 IH。两周的 IH 增加了两种小鼠心脏组织中的 O-GlcNAc 酰化，而 Ogt-Tg 小鼠中的 O-GlcNAc 酰化在常氧和 IH 条件下均显着高于 WT 小鼠。 WT 小鼠在 IH 后表现出心脏重塑，而 Ogt-Tg 小鼠的心脏重塑显着减弱。 IH 后，两种小鼠品系的氧化应激和细胞凋亡均增加，而 Ogt-Tg 小鼠中这些过程的增加速率显着低于 WT 小鼠。为了研究 IH 后 Ogt-Tg 小鼠心脏重塑减弱的机制，测定了 O-GlcNA 酰化对活化 T 细胞主调节核因子 (NFAT) 和 NF-κB 活性的影响。 GSK-3β（NFAT 的负调节因子）的 O-GlcNA 酰化在 Ogt-Tg 小鼠中显着增加，而 GSK-3β 的磷酸化则相反减少。对于 NF-κB p65 观察到相同的结果。体外报告基因测定表明，O-GlcNAcase 抑制剂增强的 O-GlcNAc 酰化抑制了 NFAT 和 NF-κB 启动子活性。这些数据表明，增强的O-GlcNA糖化通过GSK-3β和NF-κB p65的O-GlcNA糖化抑制NFAT和NF-κB活性来减轻IH诱导的心脏重塑。
Type 2 diabetes mellitus (T2DM) has been reported to be associated with cardiac remodeling. AlthoughO-GlcNAcylation is known to be elevated in diabetic and ischemic hearts, the effects ofO-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 transgenicO-GlcNAc transferase (Ogt-Tg) mice. Two weeks of IH increasedO-GlcNAcylation in the heart tissues of both strains of mice, whereasO-GlcNAcylation inOgt-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 inOgt-Tg mice. Oxidative stress and apoptosis increased after IH in both strains of mice, whereas the rate of increase in these processes inOgt-Tg mice was significantly lower than that in WT mice. To examine the mechanism of cardiac remodeling attenuation inOgt-Tg mice after IH, the effects ofO-GlcNAcylation on the activities of the master regulators nuclear factor of activated T cells (NFAT) and NF-κB were determined. TheO-GlcNAcylation of GSK-3β, a negative regulator of NFAT, was significantly increased inOgt-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 ofO-GlcNAcylation by anO-GlcNAcase inhibitor suppressed NFAT and NF-κB promoter activity. These data suggest that augmentedO-GlcNAcylation mitigates IH-induced cardiac remodeling by suppressing NFAT and NF-κB activities through theO-GlcNAcylation of GSK-3β and NF-κB p65.
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影响因子：
--
作者：
G. Hart;K. D. Greis;L. Dong;M. A. Blomberg;T. Chou;M. Jiang;E. Roquemore;Diane M. Snow;
通讯作者：
G. Hart;K. D. Greis;L. Dong;M. A. Blomberg;T. Chou;M. Jiang;E. Roquemore;Diane M. Snow;
DOI：
10.1016/s0021-9258(17)43295-9
发表时间：
1984-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
C R Torres;G. W. Hart
通讯作者：
C R Torres;G. W. Hart
影响因子：
37.8
作者：
Hirotani, S;Otsu, K;Hori, M
通讯作者：
Hori, M
维拉帕米对大鼠缺氧性心肌肥厚的抑制作用
影响因子：
9.5
作者：
A. Genovese;M. Chiariello;A. Cacciapuoti;W. Alfieri;S. Latte;M. Condorelli
通讯作者：
M. Condorelli
影响因子：
5
作者：
Liu, J;Pang, Y;Marchase, RB
通讯作者：
Marchase, RB