OKA Takafumii ≪Cardiovascular Medicine≫ “Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure”

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PublishNature, 485, 251-255 (2012)

Heart failure is the terminal state of all heart diseases and leading cause of mortality in industrialized country. The involvement of inflammation with the pathogenesis of heart failure has been reported, although infection with microorganism is not involved in most cases. Unmethylated CpG motifs are contained in bacterial DNA and mitochondrial DNA, and they trigger inflammation through Toll-like Receptor 9 (TLR9). Mitochondria are degraded by autophagy/lysosomal system. We hypothesized that accumulation of mitochondrial DNA causes inflammation in failing hearts. In wild-type mice, the inflammatory cell infiltration and DNA accumulation in autolysosome were observed in pressure-overload induced failing hearts. Deoxyribonuclease II (DNase II) is endonuclease that degrades mitochondrial DNA in autolysosome. We generated cardiac-specific DNase II deficient mice. After pressure-overload operation, DNase II deficient hearts showed heart failure, inflammatory responses, and accumulation of mitochondrial DNA, which was attenuated by TLR9 ablation. Furthermore, we demonstrated the involvement of TLR9 signaling with heart failure in wild-type mice with normal DNase II allele. This study elucidated the new mechanism of heart failure, DNase II-TLR9 axis.