Hyper-O-GlcNAcylation impairs insulin response against reperfusion-induced myocardial injury and arrhythmias in obesity
Hyper-O-GlcNAcylation impairs insulin response against reperfusion-induced myocardial injury and arrhythmias in obesity
复制标题
高 O-GlcNAc 酰化会损害胰岛素对肥胖再灌注引起的心肌损伤和心律失常的反应
DOI：
10.1016/j.bbrc.2021.04.066
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发表时间：
2021-04-26
影响因子：
3.1
通讯作者：
Zheng, Qiangsun
中科院分区：
文献类型：
--
作者：
Jin, Lingyan;Gao, Feng;Zheng, Qiangsun
心肌缺血/再灌注(I/R)损伤是心脏病治疗患者发病率和死亡率的主要决定因素。据报道，各种治疗方法都对再灌注损伤有好处，但它们对肥胖的心脏保护作用似乎有所减弱，其潜在机制仍不清楚。在本研究中，我们发现db/db小鼠表现出心脏高-O-GlcN酰化。同时，在H9c2细胞中，棕榈酸酯处理(200 mM；12h)显示整体蛋白O-GlcN酰化增加，同时对再灌注损伤的胰岛素反应受损。为了研究O-GlcN酰化是否是这种现象的基础，使用氨基葡萄糖来增加全球蛋白质O-GlcNAc的水平。有趣的是，组织学染色、电生理研究、血清心脏标志物和氧化应激生物标志物分析表明，缺血前使用氨基葡萄糖可减弱对心肌梗死、心律失常和氧化应激的胰岛素心脏保护作用。从机制上讲，氨基葡萄糖治疗减少了胰岛素刺激的Akt磷酸化，Akt是细胞存活的关键调节因子。此外，6-重氮-5-氧代-L去亮氨酸(DON)抑制O-GlcN酰化可明显增加胰岛素诱导的Akt磷酸化，并恢复其对棕榈酸酯诱导的胰岛素抵抗H9c2细胞再灌注损伤的心脏保护作用。我们的发现表明，肥胖诱导的高-O-GlcN酰化可能有助于减弱胰岛素对心肌I/R损伤的保护作用。(C)2021 Elsevier Inc.保留所有权利。
Myocardial ischemia/reperfusion (I/R) injury is a major determinant of morbidity and mortality in patients undergoing treatment for cardiac disease. A variety of treatments are reported to have benefits against reperfusion injury, yet their cardioprotective effects seem to be diminished in obesity, and the underlying mechanism remains elusive. In this study, we found that db/db mice exhibit cardiac hyper-O-GlcNAcylation. In parallel, palmitate treatment (200 mM; 12 h) in H9c2 cells showed an increase in global protein O-GlcNAcylation, along with an impaired insulin response against reperfusion injury. To investigate whether O-GlcNAcylation underlies this phenomenon, glucosamine was used to increase global protein O-GlcNAc levels. Interestingly, histological staining, electrophysiological studies, serum cardiac markers and oxidative stress biomarker assays showed that preischemic treatment with glucosamine attenuated insulin cardioprotection against myocardial infarction, arrhythmia and oxidative stress. Mechanistically, glucosamine treatment decreased insulin-stimulated Akt phosphorylation, a key modulator of cell survival. Furthermore, inhibition of O-GlcNAcylation via 6-diazo-5-oxo-L-norleucine (DON) apparently increased insulin-induced Akt phosphorylation and restored its cardioprotective response against reperfusion injury in palmitate-induced insulin-resistant H9c2 cells. Our findings demonstrated that obesity-induced hyper-O-GlcNAcylation might contribute to the attenuation of insulin cardioprotection against I/R injury. (C) 2021 Elsevier Inc. All rights reserved.