通过CaMKIIδB提升的MCU表达限制了病态心脏重塑
Pei Wang1, Shangcheng Xu1, Jiqian Xu1
1Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (P.W., S.X., J.X., Y.X., H.Z., B.Z., R.T., W.W.), University of Washington, Seattle.
Circulation
|February 15, 2022
概括
激活线粒体单载体 (MCU) 保护心脏免受压力引起的损伤. 这种补偿机制保持平衡和心肌细胞存活率,防止心力衰竭.
科学领域:
- 心血管生物学 心血管生物学
- 线粒体生理学线粒体生理学
- 心脏病理生理学 心脏病理生理学
背景情况:
- (Ca2+) 对于细胞能量代谢至关重要.
- 线粒体Ca2+过载通过破坏心肌细胞导致心力衰竭.
- 线粒体Ca2+单载体 (MCU) 在调节线粒体Ca2+吸收方面发挥着关键作用.
研究的目的:
- 为了研究 mitochondrial Ca2+ uniporter (MCU) 在慢性压力下的调节.
- 确定MCU在由β-上腺刺激诱导的病态心脏重塑中的作用.
- 阐明心脏应激期间参与MCU调节的信号通路.
主要方法:
- 利用了MCU淘汰赛和转基因小鼠模型.
- 使用异二醇 (ISO) 诱导慢性心脏压力 in vivo 和 in vitro.
- 评估心脏功能,多,纤维化和心肌细胞死亡.
- 在培养心肌细胞中采用腺病毒介导的基因操纵.
主要成果:
- 异二醇 (ISO) 增加了MCU水平和心脏线粒体中的线粒体Ca2+吸收.
- 缺乏MCU的小鼠在ISO治疗后表现出恶化的心脏缩,纤维化和心肌细胞死亡.
- 过度表达MCU可以保持心脏功能,并防止ISO诱导的心脏重塑.
- 确定了Ca2+/calmodulin kinase II deltaB (CaMKIIδB) /CREB通路作为MCU基因表达的关键调节者.
结论:
- β-上腺素受体/CaMKIIδB/CREB通路在心脏上调节了MCU的表达.
- 增加的MCU水平作为对病态心脏重塑的补偿机制.
- 通过MCU维持线粒体Ca2+稳态对于心肌细胞存活和在压力下心脏功能至关重要.
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