Zhang, D., Hu, X., Li, J., Liu, J., Baks-Te Bulte, L., Wiersma, M., Malik, N.U., van Marion, D.M.S., Tolouee, M., Hoogstra-Berends, F., Lanters, E.A.H., van Roon, A.M., de Vries, A.A.F., Pijnappels, D.A., de Groot, N.M.S., Henning, R.H., Brundel, B.J.J.M. (2019). DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation.  Nat. Commun. 10(1): 1307.

FBrf0241864

Research paper

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.

PMC6428932 (PMC) (EuropePMC)