糖尿病高血糖症激活了CaMKII和心律失常,通过O-链 glycosylation
Jeffrey R Erickson1, Laetitia Pereira, Lianguo Wang
1Department of Pharmacology, University of California, Davis, Davis, California 95616, USA.
Nature
|October 1, 2013
概括
高血糖 (高血糖) 通过O-链接的N-乙糖胺 (O-GlcNAc) 来改变Ca2+/卡尔莫杜林依赖蛋白激酶II (CaMKII). 这种修改促进了CaMKII的激活,导致糖尿病患者的心脏和大脑功能障碍.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 心血管科学 心血管科学
背景情况:
- 卡二+/卡尔莫杜林依赖蛋白激酶II (CaMKII) 在心脏和神经元功能中起着至关重要的作用.
- 慢性CaMKII激活与心力衰竭等病理状况有关.
- 糖尿病是心血管和神经退行性疾病的重要危险因素.
研究的目的:
- 研究一种新的机制,将CaMKII和糖尿病中的高血糖信号连接起来.
- 阐明O链接N-乙糖胺 (O-GlcNAc) 修饰在高血糖症期间CaMKII活性中的作用.
- 确定这种途径对糖尿病心脏病理生理学的贡献.
主要方法:
- 在人类,老鼠和小鼠模型中研究了O-GlcNAc的CaMKII修饰.
- 在高葡萄糖条件下,评估了心肌细胞中的CaMKII激活和质网膜Ca2+) 释放.
- 利用了O-GlcNAc信号的药理抑制和CaMKIIδ.的遗传移除.
- 在完整的输血心脏和糖尿病动物模型中检查了心律失常.
主要成果:
- 急性高血糖症诱导O-GlcNAc对CaMKII在Ser279的修饰,导致自主激活.
- 在糖尿病患者和老鼠的心脏和大脑中,O-GlcNAc修饰的CaMKII水平升高.
- 增加的葡萄糖增强了心肌细胞中依赖于CaMKII的自发Ca2+释放,导致心脏功能障碍和心律失常.
- 对CaMKIIδ的药理抑制或遗传除可以防止这些高血糖引起的效应.
- 糖尿病动物的心律失常会因高葡萄糖而加剧,而O-GlcNAc阻塞则会抑制.
结论:
- CaMKII的O-GlcNAc修饰代表了一种由高血糖症激活的新信号通路.
- 这种修改有助于糖尿病的心脏和神经元病理生理学.
- 针对O-GlcNAc信号可能为影响心脏和大脑的糖尿病并发症提供治疗策略.
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