DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD⁺ depletion in experimental atrial fibrillation.

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 activation in response to oxidative DNA damage. synthesis of ADP-ribose chains in turn depletes nicotinamide adenine dinucleotide (NAD⁺), induces further DNA damage and contractile dysfunction. Accordingly, NAD⁺ replenishment or depletion precludes functional loss. Moreover, inhibition of Pduanyu371 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 Pduanyu371 activity. The findings uncover a mechanism by which tachypacing impairs cardiomyocyte function and implicates Pduanyu371 as a possible therapeutic target that may preserve cardiomyocyte function in clinical AF.

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