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Cardiac O-GlcNAcylation blunts autophagic signaling in the diabetic heart

机译：心脏O-GlcNAcylation减弱了糖尿病心脏的自噬信号

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Aims: Increased O-linked attachment of ??-N-acetylglucosamine (O-GlcNAc) to proteins has been implicated in the adverse effects of diabetes on the heart, although this has typically been based on models of severe hyperglycemia. Diabetes has also been associated with dysregulation of autophagy, a critical cell survival process; however, little is known regarding autophagy in the diabetic heart or whether this is influenced by O-GlcNAcylation or hemodynamic stress. Main methods: Young male rats were assigned to control (12% kcal fat/19% protein/69% carbohydrate), high fat diet (60/19/21%) and type 2 diabetic (high fat diet + low dose streptozotocin) groups for 8 weeks, followed by sham or pressure overload surgeries; animals were sacrificed 8 weeks after surgery. Key findings: A modest increase in arterial pressure resulted in no significant effects on cardiac function in control or high fat groups, while diabetic hearts exhibited contractile dysfunction and increased apoptosis and scar formation. Immunoprecipitation studies revealed, for the first time, that Beclin-1, which plays a critical early role in autophagy, and the anti-apoptotic Bcl-2, are targets for O-GlcNAcylation. Interestingly, we also found that cardiomyocytes isolated from type 2 diabetic db/db mice exhibited a blunted autophagic response and this was at least partially reversed by inhibiting glucose entry into the hexosamine biosynthesis pathway, which regulates O-GlcNAc synthesis. We also found that acutely augmenting O-GlcNAc levels in non-diabetic cardiomyocytes mimicked the effects of diabetes by blunting autophagic signaling. Significance: These data suggest that O-GlcNAc-mediated inhibition of autophagy may contribute to the abnormal response of diabetic hearts to hemodynamic stress. ? 2012 Elsevier Inc.
机译：目的：??-N-乙酰氨基葡萄糖（O-GlcNAc）与蛋白质的O-连接增加与糖尿病对心脏的不良反应有关，尽管这通常是基于严重的高血糖模型。糖尿病还与自噬失调有关，自噬是关键的细胞存活过程。然而，关于糖尿病心脏中的自噬或它是否受O-GlcNAcylation或血液动力学压力的影响知之甚少。主要方法：将雄性雄性大鼠分为对照组（12％大卡脂肪/ 19％蛋白质/ 69％碳水化合物），高脂饮食（60/19/21％）和2型糖尿病（高脂饮食+低剂量链脲佐菌素）组持续8周，然后进行假手术或压力超负荷手术;手术后8周将动物处死。主要发现：动脉压的适度升高对对照组或高脂人群的心脏功能没有明显影响，而糖尿病心脏表现出收缩功能障碍，凋亡和疤痕形成增加。免疫沉淀研究首次表明，在自噬中起关键作用的Beclin-1和抗凋亡Bcl-2是O-GlcNAcylation的靶标。有趣的是，我们还发现从2型糖尿病db / db小鼠中分离出的心肌细胞显示钝化的自噬反应，并且通过抑制葡萄糖进入调节O-GlcNAc合成的己糖胺生物合成途径而至少部分逆转了自噬反应。我们还发现，非糖尿病性心肌细胞中O-GlcNAc水平的急剧增加通过钝化自噬信号传导来模仿糖尿病的影响。意义：这些数据表明，O-GlcNAc介导的自噬抑制作用可能导致糖尿病心脏对血流动力学压力的异常反应。 ？ 2012爱思唯尔公司

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