来自爱荷华大学卡佛医学院的研究小组找到了CaM激酶II促发心脏细胞死亡,进而导致心脏损伤的机制,并指出这一过程发生在细胞产生能量的线粒体中。动物试验证明,抑制该酶的活性能够避免心脏细胞死亡,保护动物免于发展为心脏衰竭。相关结果发表在Nature杂志上。

-2012年11月8日《自然》

中文翻译


【题目】心脏中CaMKII决定线粒体应激反应

【译文】心肌细胞死亡由过度线粒体的Ca2+输入而启动,而Ca2+输入是由Ca2+超载、渗透性转换孔(mPTP)的打开以及线粒体内膜电位(ΔΨm)的损耗造成的。然而,控制通过内膜线粒体Ca2+单输送体(MCU)的线粒体Ca2+输入的信号通路尚不清楚。 线粒体Ca2+/钙调节素依赖的蛋白激酶II (CaMKII)在心肌死亡和心脏衰竭常见原因如缺血再灌注、心肌梗塞及神经元介质损伤中被激活;这些发现表明CaMKII可以将疾病应激和线粒体损伤相联系。本研究表明CaMKII可通过增加MCU电流(IMCU)促进mPTP打开以及心肌死亡。线粒体靶向的CaMKII抑制性蛋白或环孢霉素A(一种缺血再灌注损伤中具有临床效应的mPTP拮抗剂)同样可以阻止mPTP的打开、ΔΨm受损,并降低应答缺血再灌注损伤时的线粒体破坏和程序性细胞死亡。具有心肌和线粒体靶向的CaMKII抑制作用的小鼠减少了IMCU,对缺血再灌注损伤、心肌梗塞和神经元介质损伤耐受,表明CaMKII的病理作用本质上是由增加的IMCU所介导的。我们的发现证实CaMKII活性是心肌细胞死亡中线粒体Ca2+输入的核心机制,并表明线粒体靶向的CaMKII抑制作用可以阻止或减少当应答病理生理应激常见实验形式时的心肌死亡及心脏衰竭。

英文原稿


[Title]: CaMKII determines mitochondrial stress responses in heart

 [Authors]:Mei-ling A. Joiner,1 Olha M. Koval,1 Jingdong Li,1, 8 B. Julie He,1, 2 Chantal Allamargot,3 Zhan Gao,1 Elizabeth D. Luczak,1 Duane D. Hall,1 Brian D. Fink,4 Biyi Chen,1 Jinying Yang,1 Steven A. Moore,2, 5 Thomas D. Scholz,6 Stefan Strack,7 Peter J. Mohler,1, 8 William I. Sivitz,1, 4 Long-Sheng Song1 & Mark E. Anderson1, 2

[Abstract]:Myocardial cell death is initiated by excessive mitochondrial Ca2+ entry causing Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm). However, the signalling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU) are not known. The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated in ischaemia reperfusion, myocardial infarction and neurohumoral injury, common causes of myocardial death and heart failure; these findings suggest that CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (IMCU). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A, an mPTP antagonist with clinical efficacy in ischaemia reperfusion injury, equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to ischaemia reperfusion injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition have reduced IMCU and are resistant to ischaemia reperfusion injury, myocardial infarction and neurohumoral injury, suggesting that pathological actions of CaMKII are substantially mediated by increasing IMCU. Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca2+ entry in myocardial cell death, and indicate that mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure in response to common experimental forms of pathophysiological stress.

原文地址

http://www.nature.com/nature/journal/v491/n7423/full/nature11444.html

 

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