Nature：抑制酶CaMKII活性有望治疗心脏病

美国爱荷华大学研究人员之前已证实在心脏病发作或患上其他导致心肌损伤的疾病之后，一种被称作钙调蛋白激酶II(CaM kinase II, CaMKII)在心脏细胞死亡中发挥着至关重要的作用。跳动着的心脏细胞缺失通常是永久性的，从而导致心脏病。

如今，在爱荷华大学卡佛医学院内科医学教授Mark Anderson博士的领导下，研究人员全力研究在心脏受损之后，CaMKII如何触发心脏细胞死亡，并证实它作用于心脏细胞内产生能量的线粒体。在动物测试中，研究人员报道，阻断这种酶能够阻止心脏细胞死亡，并且保护这些动物免受心脏病。

在心脏细胞中，线粒体产生的能量引发每次心跳。然而，当心脏受损时，线粒体不完整并且不能发挥正常功能，从而触发细胞死亡和心脏病。

论文第一作者Mei-ling Joiner博士说，“我们发现当心脏受损时，线粒体中酶CaMKII的活性促进细胞死亡。这些发现可能有助于我们开发出治疗心脏病的方法和降低心脏病发作后的死亡率。”

这项新研究表明激活的CaMKII促进线粒体发生泄漏，并且通过允许太多的钙离子进入线粒体来促进心肌遭受更大的损伤。特别地，研究人员发现CaMKII通过修饰一种特殊的线粒体钙离子通道来调节钙离子进入线粒体。酶CaMKI活性增加过大会增加流进线粒体中的钙离子数量，而这种钙离子超载触发细胞死亡。

利用经过基因修饰的小鼠，研究人员也证实抑制线粒体中的CaMKII活性能够阻止钙离子超载，降低对线粒体的破坏，从而在心脏病发作期间，阻止小鼠的心脏细胞死亡。

这些发现有助于人们深入认识线粒体功能的分子机制，并表明抑制线粒体中的酶CaMKII可能导致人们开发出新的更加有效的疗法来治疗常见性的心脏病。

CaMKII determines mitochondrial stress responses in heart

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)1, 2. However, the signalling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU)3, 4, 5 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 injury6, 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.