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.
Highlights
Cardiac diseases, a class of disorders affecting biological structure and/or physiological function of the heart, are the leading cause of morbidity and mortality worldwide
A recent study revealed a significant and consistent increase of nuclear and mitochondrial DNA damage in experimental and human atrial fibrillation (AF), where the recruitment of nuclear DNA repair machineries was occurring by activation of poly-ADP-ribose polymerase 1 (PARP1), a major NAD+ consumer [26]
When nicotinamide mononucleotide (NMN) is provided during ischemia, glycolysis is increased to facilitate ATP production, promoting cardioprotection, while if NMN is given during reperfusion, it protects the heart by enhancing acidosis, which is known to be cardioprotective during early reperfusion via a shutdown of mitochondrial permeability transition pore to maintain the mitochondrial membrane potential and ATP balance [217,218]
Summary
A class of disorders affecting biological structure and/or physiological function of the heart, are the leading cause of morbidity and mortality worldwide. AF, the most common heart rhythm disorder, is characterized by the rapid and irregular beating of the upper atrial chambers due to the electrical, structural, and functional remodeling of atrial cardiomyocytes [3,4] This arrhythmia can result in static atrial blood, promoting the formation of atrial thrombi and triggering detrimental symptoms, such as stroke, arterial embolization, and a reduced quality of life [5,6,7]. Apart from well-known environmental or genetic mutation-mediated risk factors associated with AF and IHD [16,17,18], recent evidence suggests that oxidative stress-induced DNA damage occurs and plays a key role in the pathophysiology of these two cardiac diseases [19,20,21]. Unconverted superoxide and high levels of hydrogen peroxide and other ROS lead to cell damage or death mainly by altering membrane and DNA integrity [47], which are characteristics of oxidative stress. Oxidative DNA damage encompassed both nuclear DNA damage and mitochondrial DNA damage, which are both involved in the pathogenesis of various cardiac diseases, including AF and IHD
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