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

作者：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 · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-09014-2 · 被引用次数：161 · 研究领域：PARP inhibition in cancer therapy、Electrostatic Discharge in Electronics、Integrated Circuits and Semiconductor Failure Analysis

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.