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

Deli Zhang, Xu Hu, Jin Li, Jia Liu, Luciënne 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, Daniël A Pijnappels, Natasja M S de Groot, Robert H Henning, Bianca J J M Brundel

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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
JournalNature communications
Issue number1
Publication statusPublished - 1 Dec 2019

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