DNA single-strand break-induced DNA damage response causes heart failure

Tomoaki Higo, Atsuhiko T. Naito (), Tomokazu Sumida, Masato Shibamoto, Katsuki Okada, Seitaro Nomura, Akito Nakagawa, Toshihiro Yamaguchi, Taku Sakai, Akihito Hashimoto, Yuki Kuramoto, Masamichi Ito, Shungo Hikoso, Hiroshi Akazawa, Jong-Kook Lee, Ichiro Shiojima, Peter J. McKinnon, Yasushi Sakata and Issei Komuro ()
Additional contact information
Tomoaki Higo: Osaka University Graduate School of Medicine
Atsuhiko T. Naito: Osaka University Graduate School of Medicine
Tomokazu Sumida: CREST
Masato Shibamoto: Osaka University Graduate School of Medicine
Katsuki Okada: Osaka University Graduate School of Medicine
Seitaro Nomura: CREST
Akito Nakagawa: Osaka University Graduate School of Medicine
Toshihiro Yamaguchi: The University of Tokyo Graduate School of Medicine
Taku Sakai: Osaka University Graduate School of Medicine
Akihito Hashimoto: Osaka University Graduate School of Medicine
Yuki Kuramoto: Osaka University Graduate School of Medicine
Masamichi Ito: The University of Tokyo Graduate School of Medicine
Shungo Hikoso: Osaka University Graduate School of Medicine
Hiroshi Akazawa: Osaka University Graduate School of Medicine
Jong-Kook Lee: Osaka University Graduate School of Medicine
Ichiro Shiojima: CREST
Peter J. McKinnon: ST. Jude Children’s Research Hospital
Yasushi Sakata: Osaka University Graduate School of Medicine
Issei Komuro: CREST

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract The DNA damage response (DDR) plays a pivotal role in maintaining genome integrity. DNA damage and DDR activation are observed in the failing heart, however, the type of DNA damage and its role in the pathogenesis of heart failure remain elusive. Here we show the critical role of DNA single-strand break (SSB) in the pathogenesis of pressure overload-induced heart failure. Accumulation of unrepaired SSB is observed in cardiomyocytes of the failing heart. Unrepaired SSB activates DDR and increases the expression of inflammatory cytokines through NF-κB signalling. Pressure overload-induced heart failure is more severe in the mice lacking XRCC1, an essential protein for SSB repair, which is rescued by blocking DDR activation through genetic deletion of ATM, suggesting the causative role of SSB accumulation and DDR activation in the pathogenesis of heart failure. Prevention of SSB accumulation or persistent DDR activation may become a new therapeutic strategy against heart failure.

Date: 2017
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DOI: 10.1038/ncomms15104

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