Augmented O-GlcNAcylation exacerbates right ventricular dysfunction and remodeling via enhancement of hypertrophy, mitophagy, and fibrosis in mice exposed to long-term intermittent hypoxia
Augmented O-GlcNAcylation exacerbates right ventricular dysfunction and remodeling via enhancement of hypertrophy, mitophagy, and fibrosis in mice exposed to long-term intermittent hypoxia
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DOI：
10.1038/s41440-022-01088-8
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发表时间：
2022-11
影响因子：
5.4
通讯作者：
Shunichi Yokoe;T. Hayashi;T. Nakagawa;R. Kato;Y. Ijiri;Takehiro Yamaguchi;Y. Izumi;M. Yoshiyama;M. Asahi
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文献类型：
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作者：
Shunichi Yokoe;T. Hayashi;T. Nakagawa;R. Kato;Y. Ijiri;Takehiro Yamaguchi;Y. Izumi;M. Yoshiyama;M. Asahi
在此之前，我们发现，通过糖原合成酶激酶3β (GSK-3β)和NF-κB p65的o - glcn酰化抑制活化T细胞核因子（NFAT）和核因子κB (NF-κB)，增强了o - glcn酰化（o - glcn酰化）连接的n -乙酰氨基葡萄糖化（o - glcn酰化）减轻急性（2周）间断缺氧（IH）暴露的o - glcnac转移酶转基因（Ogt-Tg）小鼠的心脏重构。由于这种效应是时间依赖性的，我们在本研究中将dogt - tg小鼠暴露于IH中4周（IH4W）。与野生型（WT）小鼠相比，暴露于常氧环境和IH4W的ogt - tg小鼠的o - glcn酰化显著增强。与正常缺氧相比，IH4W后WT和dogt - tg小鼠的totalo - glcnac酰化水平显著升高。IH4W后，Ogt-Tg小鼠右心室（rv）的心肌肥大和纤维化症状明显加重，而左心室（lv）则没有。超声心动图显示ih4w诱导的右心室功能障碍。IH4W后，ogt - tg小鼠与WT小鼠相比，磷酸化GSK-3β水平升高，而磷酸化NF-κB p65水平未受影响。与心功能障碍相关的线粒体自噬在IH4W后的ogt - tg小鼠的RVs中增加。此外，磷酸化的动力蛋白相关蛋白1 （p-Drp1）水平显著升高，mitofusin-2 （MFN2）表达显著降低。在人胚胎肾细胞中，线粒体解偶联剂诱导的线粒体功能障碍在过表达ogt的细胞中加速。除了增加磷酸化Smad2的水平外，IH4W还促进了ogt - tg小鼠rv中的心脏纤维化。因此，增强的do - glcn酰化可能加重ih4w诱导的右心室功能障碍和重构，通过GSK-3β失活、p-Drp-1/MFN2比值增加和Smad2激活分别促进肥厚、线粒体自噬和纤维化。
Previously, we showed that augmentedO-linkedN-acetylglucosaminylation (O-GlcNAcylation) mitigates cardiac remodeling inO-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 theO-GlcNAcylation of glycogen synthase kinase 3 beta (GSK-3β) and NF-κB p65. Because this effect is time dependent, we exposedOgt-Tg mice to IH for 4 weeks (IH4W) in the present study.O-GlcNAcylation was significantly enhanced inOgt-Tg mice vs. wild-type (WT) mice exposed to normoxia and IH4W. TotalO-GlcNAcylation levels were significantly increased in WT andOgt-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 inOgt-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 ofOgt-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 inOgt-overexpressing cells. In addition to increasing the levels of phosphorylated Smad2, IH4W promoted cardiac fibrosis in the RVs ofOgt-Tg mice. Thus, augmentedO-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.