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 U.A. 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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

108 Citations (Scopus)

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
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019
Externally publishedYes

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