Nature：线粒体DNA在心脏衰竭中起着关键作用

据一项由英国国王学院伦敦和日本大阪大学研究人员完成的研究证实：心脏自身细胞的DNA在心脏衰竭患者错误激活人体免疫系统中作用起着重要作用。

科学家发现心脏衰竭影响了75万多英国人，线粒体DNA可以启动人体对感染的自然反应，以此在心脏衰竭中作出贡献。

心脏衰竭患者的免疫细胞侵入心脏，这一过程称为炎症。这个过程使得心脏肌肉的工作效率降低，减少心脏向身体其他部位泵血能力。当身体正面临如由细菌或病毒感染的威胁时，炎症才会被激活。

这项研究将刊登在Nature杂志上，研究显示在小鼠动物模型中，小鼠自身的DNA可造成心脏炎症。当吞噬过程效率变得越来越低时，DNA会逃脱这一过程。当细胞处于压力之下时如心脏衰竭过程，自噬会停止正常工作。

DNA的问题来自心脏细胞的能源生成结构——线粒体。线粒体DNA引发炎症，因为它类似于细菌的DNA，激发免疫细胞受体——Toll样受体9。

伦敦大学国王学院Kinya Otsu教授领导了这项研究，他说：当线粒体由压力等原因损坏时如心脏衰竭的过程中，这些线粒体会出现问题，因为它们的DNA仍保留一种古老的细菌指纹去动员身体的防御系统。

我们以前发现当细胞破裂时的自然过程变得不那么有效时，受损的线粒体在心脏衰竭过程积聚。现在，我们已经表明我们保留在我们的线粒体中的DNA指纹图谱使我们自身的免疫系统反抗我们。

Shannon Amoils博士说：这个有趣的发现是一个重要的突破，便于我们理解为什么在心脏衰竭，免疫系统在没有任何明显的外部威胁存在下也会被激活。

doi:10.1038/nature10992
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Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure

Takafumi Oka,Shungo Hikoso,Osamu Yamaguchi,Manabu Taneike,Toshihiro Takeda, et al.

Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure¹. However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA^{2, 3, 4}. Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes⁵. Here we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts showed infiltration of inflammatory cells and increased messenger RNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA⁶, or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9 ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.