DNA Damage, an Innocent Bystander in Atrial Fibrillation and Other Cardiovascular Diseases?

Abstract

Atrial Fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF is difficult to treat and therefore there is a great need to dissect root causes of AF with the ultimate goal to develop mechanism-based (drug) therapies. New findings related to mechanisms driving AF progression indicate a prime role for DNA damage-induced metabolic remodeling. A recent study uncovered that AF results in oxidative DNA damage and consequently excessive poly-ADP-ribose polymerase 1 (PARP1) activation and nicotinamide adenine dinucleotide (NAD⁺) depletion and finally atrial cardiomyocyte electrical and contractile dysfunction. This newly elucidated role of DNA damage in AF opens opportunities for novel therapeutic strategies. Recently developed PARP inhibitors, such as ABT-888 and olaparib, provide beneficial effects in limiting experimental AF, and are also found to limit atherosclerotic coronary artery disease and heart failure. Another therapeutic option to protect against AF is to replenish the NAD⁺ pool by supplementation with NAD⁺ or its precursors, such as nicotinamide and nicotinamide riboside. In this review, we describe the role of DNA damage-mediated metabolic remodeling in AF and other cardiovascular diseases, discuss novel druggable targets for AF and highlight future directions for clinical trials with drugs directed at PARP1-NAD⁺ pathway with the ultimate aim to preserve quality of life and to attenuate severe complications such as heart failure or stroke in patients with AF.

Keywords: DNA damage; PARP; atrial cardiomyopathy; atrial fibrillation; dilated cardiomyopathy; lamin a/c; metabolism; peripartum cardiomyopathy.

Figure 1

Structure and function of PARP1. PARP1 contains three functional domains: DNA-binding, auto-modification and catalytic domain. The three zinc fingers are responsible for recognizing aberrances in DNA molecule, followed by binding to it. In the center, the auto-modification domain permits PARylation of PARP itself. Finally, the catalytic domain carries the PARP signature and is responsible for transferring ADP-ribose subunits from nicotinamide adenine dinucleotide (NAD⁺) to PAR onto nuclear acceptor proteins.

Figure 2

DNA damage-PARP1-NAD⁺ axis is involved in AF and additional cardiovascular diseases. AF causes disruption of the microtubule network, DNA damage, PARP1 activation and excessive depletion of the NAD⁺ levels resulting in ATP depletion and ROS production in the mitochondria. This mechanism is driving AF, Interestingly, comparable mechanism is obverved in LMNA mutation-induced DCM and PPCM as well as atherosclerotic CAD. Importantly, AF is often associated with these cardiovascular diseases, and vice versa indicating that mechanisms driving these cardiac diseases may the enhance each other. Key modulators within this axis are druggable targets as conservation of the cytoskeletal network with the HSP-inducer geranylgeranylacetone (GGA), PARP1 inhibitors ABT-888 and olaparib and precursor of NAD⁺, nicotinamide protect against AF, CAD, DCM, and PPCM.