TY - JOUR
T1 - DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD + depletion in experimental atrial fibrillation
AU - Zhang, Deli
AU - Hu, Xu
AU - Li, Jin
AU - Liu, Jia
AU - Baks-te Bulte, Luciënne
AU - Wiersma, Marit
AU - Malik, Noor U.A.
AU - van Marion, Denise M.S.
AU - Tolouee, Marziyeh
AU - Hoogstra-Berends, Femke
AU - Lanters, Eva A.H.
AU - van Roon, Arie M.
AU - de Vries, Antoine A.F.
AU - Pijnappels, Daniël A.
AU - de Groot, Natasja M.S.
AU - Henning, Robert H.
AU - Brundel, Bianca J.J.M.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-019-09014-2
DO - 10.1038/s41467-019-09014-2
M3 - Article
C2 - 30898999
AN - SCOPUS:85063274057
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1307
ER -