DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD(+) depletion in experimental atrial fibrillation

Deli Zhang, Xu Hu, Jin Li, Jia Liu, Lucienne Baks-te Bulte, Marit Wiersma, Noor-ul-Ann Malik, Denise M. S. van Marion, Marziyeh Tolouee, Femke Hoogstra-Berends, Eva A. H. Lanters, Arie M. van Roon, Antoine A. F. de Vries, Daniel A. Pijnappels, Natasja M. S. de Groot, Robert H. Henning, Bianca J. J. M. Brundel

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Abstract

Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF progression is driven by derailment of protein homeostasis, which ultimately causes contractile dysfunction of the atria. Here we report that tachypacing-induced functional loss of atrial cardiomyocytes is precipitated by excessive poly(ADP)-ribose polymerase 1 (PARP1) activation in response to oxidative DNA damage. PARP1-mediated synthesis of ADP-ribose chains in turn depletes nicotinamide adenine dinucleotide (NAD(+)), induces further DNA damage and contractile dysfunction. Accordingly, NAD(+) replenishment or PARP1 depletion precludes functional loss. Moreover, inhibition of PARP1 protects against tachypacing-induced NAD(+) depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila. Consistently, cardiomyocytes of persistent AF patients show significant DNA damage, which correlates with PARP1 activity. The findings uncover a mechanism by which tachypacing impairs cardiomyocyte function and implicates PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in clinical AF.

Original languageEnglish
Article number1307
Number of pages17
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 21-Mar-2019

Keywords

  • POLY(ADP-RIBOSE) POLYMERASE INHIBITOR
  • MYOCYTE CELL-DEATH
  • CONTRACTILE DYSFUNCTION
  • REPERFUSION INJURY
  • STRUCTURAL-CHANGES
  • HEART-FAILURE
  • NICOTINAMIDE
  • DROSOPHILA
  • MODEL
  • PROTEOSTASIS

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