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 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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number1307
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Cite this

Zhang, Deli ; Hu, Xu ; Li, Jin ; Liu, Jia ; Baks-Te Bulte, Luciënne ; Wiersma, Marit ; Malik, Noor-Ul-Ann ; van Marion, Denise M S ; Tolouee, Marziyeh ; Hoogstra-Berends, Femke ; Lanters, Eva A H ; van Roon, Arie M ; de Vries, Antoine A F ; Pijnappels, Daniël A ; de Groot, Natasja M S ; Henning, Robert H ; Brundel, Bianca J J M. / DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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title = "DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation",
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.",
author = "Deli Zhang and Xu Hu and Jin Li and Jia Liu and {Baks-Te Bulte}, Luci{\"e}nne and Marit Wiersma and Noor-Ul-Ann Malik and {van Marion}, {Denise M S} and Marziyeh Tolouee and Femke Hoogstra-Berends and Lanters, {Eva A H} and {van Roon}, {Arie M} and {de Vries}, {Antoine A F} and Pijnappels, {Dani{\"e}l A} and {de Groot}, {Natasja M S} and Henning, {Robert H} and Brundel, {Bianca J J M}",
year = "2019",
month = "12",
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doi = "10.1038/s41467-019-09014-2",
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Zhang, D, Hu, X, Li, J, Liu, J, Baks-Te Bulte, L, Wiersma, M, Malik, N-U-A, van Marion, DMS, Tolouee, M, Hoogstra-Berends, F, Lanters, EAH, van Roon, AM, de Vries, AAF, Pijnappels, DA, de Groot, NMS, Henning, RH & Brundel, BJJM 2019, 'DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation' Nature Communications, vol. 10, no. 1, 1307. https://doi.org/10.1038/s41467-019-09014-2

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation. / Zhang, Deli; Hu, Xu; Li, Jin; Liu, Jia; Baks-Te Bulte, Luciënne; Wiersma, Marit; Malik, Noor-Ul-Ann; van Marion, Denise M S; Tolouee, Marziyeh; Hoogstra-Berends, Femke; Lanters, Eva A H; van Roon, Arie M; de Vries, Antoine A F; Pijnappels, Daniël A; de Groot, Natasja M S; Henning, Robert H; Brundel, Bianca J J M.

In: Nature Communications, Vol. 10, No. 1, 1307, 01.12.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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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-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, Daniël A

AU - de Groot, Natasja M S

AU - Henning, Robert H

AU - Brundel, Bianca J J M

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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.

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