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. Marion, Marziyeh Tolouee, Femke Hoogstra-Berends, Eva A. H. Lanters, Arie M. Roon, Antoine A. F. Vries, Daniël A. Pijnappels, Natasja M. S. Groot, Robert H. Henning and Bianca J. J. M. Brundel ()
Additional contact information
Deli Zhang: Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences
Xu Hu: Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences
Jin Li: Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences
Jia Liu: Leiden University Medical Center
Luciënne Baks-te Bulte: Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences
Marit Wiersma: Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences
Noor-ul-Ann Malik: Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences
Denise M. S. Marion: Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences
Marziyeh Tolouee: University Medical Centre Groningen, University of Groningen
Femke Hoogstra-Berends: University Medical Centre Groningen, University of Groningen
Eva A. H. Lanters: Erasmus Medical Center
Arie M. Roon: University of Groningen, University Medical Center Groningen
Antoine A. F. Vries: Leiden University Medical Center
Daniël A. Pijnappels: Leiden University Medical Center
Natasja M. S. Groot: Erasmus Medical Center
Robert H. Henning: University Medical Centre Groningen, University of Groningen
Bianca J. J. M. Brundel: Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09014-2

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