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

Nat Commun. 2017 Apr 24;8:15104. doi: 10.1038/ncomms15104.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Cytokines / immunology
  • DNA / metabolism*
  • DNA Breaks, Single-Stranded*
  • DNA Damage / genetics*
  • DNA Damage / immunology
  • DNA Repair / genetics
  • Gene Knockout Techniques
  • Heart Failure / genetics*
  • Heart Failure / immunology
  • Inflammation
  • Mice
  • Myocytes, Cardiac / immunology
  • Myocytes, Cardiac / metabolism*
  • NF-kappa B / immunology
  • X-ray Repair Cross Complementing Protein 1 / genetics*

Substances

  • Cytokines
  • NF-kappa B
  • X-ray Repair Cross Complementing Protein 1
  • Xrcc1 protein, mouse
  • DNA
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse