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.
Highlights
Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time
The findings reveal that tachypacing (TP)-induced cardiomyocyte dysfunction is a consequence of DNA damage-modulated poly(ADP)-ribose polymerase 1 (PARP1) activation, which leads to depletion of nicotinamide adenine dinucleotide (NAD+) and further oxidative stress and DNA damage and implicate PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in AF
As nicotinamide is known to inhibit the activation of PARP11,12, we tested the level of poly(ADP-ribose) polymerases (PARPs) activity by measuring the amount of poly(ADP-ribose) chains (PAR) synthesis in normal and tachypaced cardiomyocytes
Summary
Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. 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. Inhibition of PARP1 protects against tachypacing-induced NAD+ depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila. The current insight is that progression of AF is driven by the high-activation rate of atrial cardiomyocytes, inducing their electrical, structural, and functional remodeling, which renders them increasingly permissive to the arrhythmia[1]. The findings reveal that tachypacing (TP)-induced cardiomyocyte dysfunction is a consequence of DNA damage-modulated PARP1 activation, which leads to depletion of nicotinamide adenine dinucleotide (NAD+) and further oxidative stress and DNA damage and implicate PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in AF
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