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Review
. 2021 Apr 7;22(8):3838.
doi: 10.3390/ijms22083838.

Role of Oxidative DNA Damage and Repair in Atrial Fibrillation and Ischemic Heart Disease

Liangyu Hu  1 , Zhengkun Wang  1 , Claudia Carmone  1 , Jaap Keijer  1 , Deli Zhang  1
Affiliations
Review

Role of Oxidative DNA Damage and Repair in Atrial Fibrillation and Ischemic Heart Disease

Liangyu Hu et al. Int J Mol Sci. .

Abstract

Atrial fibrillation (AF) and ischemic heart disease (IHD) represent the two most common clinical cardiac diseases, characterized by angina, arrhythmia, myocardial damage, and cardiac dysfunction, significantly contributing to cardiovascular morbidity and mortality and posing a heavy socio-economic burden on society worldwide. Current treatments of these two diseases are mainly symptomatic and lack efficacy. There is thus an urgent need to develop novel therapies based on the underlying pathophysiological mechanisms. Emerging evidence indicates that oxidative DNA damage might be a major underlying mechanism that promotes a variety of cardiac diseases, including AF and IHD. Antioxidants, nicotinamide adenine dinucleotide (NAD+) boosters, and enzymes involved in oxidative DNA repair processes have been shown to attenuate oxidative damage to DNA, making them potential therapeutic targets for AF and IHD. In this review, we first summarize the main molecular mechanisms responsible for oxidative DNA damage and repair both in nuclei and mitochondria, then describe the effects of oxidative DNA damage on the development of AF and IHD, and finally discuss potential targets for oxidative DNA repair-based therapeutic approaches for these two cardiac diseases.

Keywords: DNA repair; NAD+; PARP1; antioxidant; atrial fibrillation; cardiac disease; ischemia/reperfusion injury; ischemic heart disease; oxidative DNA damage; vitamin B3.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
ROS-induced structural modifications on four DNA nucleobases—adenine, cytosine, guanine, and thymine. (a) DNA transitions and transversions. Blue lines represent transitions (changes between adenine and guanine, or cytosine and thymine). Red lines represent transversions (changes between purines and pyrimidines). (b) On top, nucleotides in DNA molecules: adenine, guanine, cytosine, thymine; and below, their major oxidized products: 8-oxo-2′-deoxyadenosine (8-oxoA), 8-oxo-2′-deoxyguanosine (8-oxoG), 5-hydroxy-2′-deoxycytidine (OH5C), and thymine glycol (Tg).
Figure 2
Figure 2
Overview of base excision repair, nucleotide excision repair and mismatch repair pathway. (a) Base excision repair (BER) pathway, including short-patch and long-patch BER sub-pathways. APE1: apurinic/apyrimidinic (AP) endonuclease 1; PAPR1: poly-ADP-ribose polymerase 1; POLB: polymerase beta; POLG: polymerase gamma; POLD/E: polymerase delta/epsilon; LIG1/3: DNA ligase I/III; FEN1: flap endonuclease 1. (b) Nucleotide excision repair (NER) pathway, including transcription-coupled NER (TC-NER) and global genome NER (GG-NER) pathways. XPC/XPD: xeroderma pigmentosum complementation group C/D; RAD23B: UV excision repair protein radiation sensitive 23 homolog B; TFIIH: transcription initiation factor IIH; ERCC1/XPF: DNA excision repair protein 1/xeroderma pigmentosum complementation group F. (c) DNA mismatch repair (MMR) pathway. MutS/MutL: DNA mismatch repair proteins; EXO1: DNA exonuclease 1; PCNA: proliferating cell nuclear antigen. Figures were adapted from Ko et al. 2012 [85], Melis et al. 2013 [95] and Brierley et al. 2013 [101].
Figure 3
Figure 3
Schematic representation of the vicious cycle of “oxidative DNA damage-excessive PARP1 activation and NAD+ depletion” in the pathophysiology of AF and potential therapeutic role of antioxidants, PARP1 inhibitors, and vitamin B3 in AF progression. Oxidative DNA damage caused by oxidative stress activates PARP1, initiating the depletion of NAD+, a key coenzyme associated with redox balance and energy metabolism. Subsequent failure to meet the increased energy demand during AF episodes further exacerbates oxidative DNA damage, and electrical and contractile dysfunction in AF, initiating a vicious cycle. Antioxidants, PARP1 inhibitors, and NAD+ replenishment by various dietary forms of vitamin B3 could preclude this vicious cycle, implicating their novel potential therapeutic role in oxidative DNA damage-induced AF. As a key antioxidative enzyme, NNT plays an important role in mitochondrial redox homeostasis under normal physiological conditions. Its mechanistic role in pathological conditions in the heart remains to be investigated. PARP1: poly-ADP-ribose polymerase 1; AF: atrial fibrillation; NAD+: nicotinamide adenine dinucleotide; NNT: nicotinamide nucleotide transhydrogenase; NA: nicotinic acid; NR: nicotinamide riboside; NAM: nicotinamide; NMN: nicotinamide mononucleotide.
Figure 4
Figure 4
Schematic relation between oxidative stress-induced DNA damage and the pathophysiology of IRI in IHD and potential therapeutic role of antioxidants, vitamin B3, and enzymes involved in DNA repair pathways in IRI treatment. Series of pathophysiological modifications during reperfusion injury stimulate net ROS emission, which induces oxidative DNA damage and activates PARP1 enzyme, resulting in depletion of intracellular NAD+. Since sirtuins depend on intracellular NAD+ for their deacetylase activity, depleted NAD+ leads to reduction in activity of sirtuins, which impairs mitochondrial functions and antioxidant defense, leading to further aggravation of IRI. Antioxidants and enhancement of oxidative stress defense and DNA repair pathways as well as NAD+ replenishment by various dietary forms of vitamin B3 could provide protection against IRI in IHD through reduction of oxidative stress and DNA damage and promotion of mitochondrial function and DNA repair capacity. IHD: ischemic heart disease; IRI: ischemia/reperfusion injury; PARP1: poly-ADP-ribose polymerase 1; ATM: ataxia telangiectasis mutated; NAD+: nicotinamide adenine dinucleotide; NA: nicotinic acid; NR: nicotinamide riboside; NAM: nicotinamide; NMN: nicotinamide mononucleotide; SOD2: superoxide dismutase 2; OGG1: 8-oxoguanine DNA glycosylase 1.
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