Excessive O-GlcNAcylation Causes Heart Failure and Sudden Death.
Excessive O-GlcNAcylation Causes Heart Failure and Sudden Death.
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过量的O-GlcN酰化会导致心力衰竭和猝死。
DOI：
10.1161/circulationaha.120.051911
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发表时间：
2021-04-27
期刊：
影响因子：
37.8
通讯作者：
Anderson ME
中科院分区：
文献类型：
--
作者：
Umapathi P;Mesubi OO;Banerjee PS;Abrol N;Wang Q;Luczak ED;Wu Y;Granger JM;Wei AC;Reyes Gaido OE;Florea L;Talbot CC Jr;Hart GW;Zachara NE;Anderson ME
心力衰竭是世界范围内死亡的主要原因，与肥胖、高血压和糖尿病的患病率上升有关。O-GlcNAc酰化是细胞内蛋白质的翻译后修饰，并作为细胞应激的代谢变阻器。除了两种酶O-GlcNAc转移酶（OGT）和O-GlcNAc酶（OGA）的净活性外，O-GlcNAc化的总水平还取决于营养和代谢通量。衰竭心肌的标志是O-GlcNAc酰化增加，但尚不清楚过度O-GlcNAc酰化是否会导致心肌病和心力衰竭。我们建立了两种新的转基因小鼠模型，心肌过表达OGT和OGA，以控制O-GlcNAc化不依赖于病理应激。我们发现OGT转基因心脏显示O-GlcNAc化增加，并发生严重的扩张型心肌病、室性心律失常和过早死亡。相比之下，OGA转基因心脏具有较低的O-GlcNAc化，但与野生型同窝对照相同的心脏功能。此外，与野生型对照相比，OGA转基因心脏对压力超负荷诱导的病理性应激具有抗性，应激后心肌O-GlcNAc化水平减弱，病理性肥大减少。OGT与OGA转基因小鼠的杂交挽救了心肌病和过早死亡，尽管心肌OGT持续升高。转录组学和功能研究显示，OGT转基因小鼠心脏中线粒体能量学受损，复合物I活性受损。复合物I活性被拯救OGA转基因杂交，这表明线粒体复合物I在O-GlcNAc介导的心脏病理中的重要作用。我们的数据提供的证据表明，过度的O-GlcNAc酰化导致心肌病，至少部分是由于能量缺陷。增强的OGA活性耐受良好，并且O-GlcNAc化的减弱有益于对抗压力超负荷诱导的病理性重塑和心力衰竭。这些发现表明，过度O-GlcNAc酰化的衰减可能代表心肌病的一种新的治疗方法。
Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension and diabetes. O-GlcNAcylation is a post-translational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. The total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Failing myocardium is marked by increased O-GlcNAcylation, but it is unknown if excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure. We developed two new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAcylation independent of pathological stress. We found that OGT transgenic hearts showed increased O-GlcNAcylation, and developed severe dilated cardiomyopathy, ventricular arrhythmias and premature death. In contrast, OGA transgenic hearts had lower O-GlcNAcylation but identical cardiac function to wild type littermate controls. Additionally, OGA transgenic hearts were resistant to pathological stress induced by pressure overload with attenuated myocardial O-GlcNAcylation levels after stress and decreased pathological hypertrophy compared to wild type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc mediated cardiac pathology. Our data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, due to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is beneficial against pressure overload induced pathologic remodeling and heart failure. These findings suggest attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.