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, Lucienne
AU - Wiersma, Marit
AU - Malik, Noor-ul-Ann
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, Daniel A.
AU - de Groot, Natasja M. S.
AU - Henning, Robert H.
AU - Brundel, Bianca J. J. M.
PY - 2019/3/21
Y1 - 2019/3/21
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.
KW - POLY(ADP-RIBOSE) POLYMERASE INHIBITOR
KW - MYOCYTE CELL-DEATH
KW - CONTRACTILE DYSFUNCTION
KW - REPERFUSION INJURY
KW - STRUCTURAL-CHANGES
KW - HEART-FAILURE
KW - NICOTINAMIDE
KW - DROSOPHILA
KW - MODEL
KW - PROTEOSTASIS
U2 - 10.1038/s41467-019-09014-2
DO - 10.1038/s41467-019-09014-2
M3 - Article
C2 - 30898999
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1307
ER -