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    • br Acknowledgements This work was

    2022-03-28


    Acknowledgements This work was financially supported by the National Natural Science Foundation of China (Grant No. 81803033) and the “Double First-Class” University project (CPU2018GF02).
    Introduction Atrial fibrillation (AF) is the most common progressive cardiac rhythm disorder. Studies have revealed an AF prevalence of approximately 3% in adults aged 20years or older, with greater prevalence in patients with risk factors, including old age, hypertension, obesity, diabetes mellitus, valvular heart disease, or heart failure, especially heart failure with preserved ejection fraction (HFpEF) [1]. One third of AF patients are hospitalized each year with an annual cost of 13 billion euros in the European Union [1]. Due to the aging population, these costs will increase dramatically unless AF is prevented and treated in a timely and effective manner. Present drug therapy for AF has moderate efficacy and important limitations, particularly due to proarrhythmic events (antiarrhythmic drugs) and bleeding complications (anticoagulants). Ablation procedures have emerged as efficient therapeutic options, but they are only efficient in the treatment of trigger-driven AF and thus cannot be applied to the majority of AF patients who suffer from substrate-mediated AF [2,3]. In the latter group, AF perpetuation is caused by electropathology, which is defined as impairment of electrical activation caused by structural and metabolic remodeling of cardiomyocytes that underlies AF progression [[2], [3], [4], [5]] (Fig. 1). Therefore, a clear and unmet need exists for a better understanding of mechanisms underlying electropathology and AF development, in order to identify novel mechanism-based treatment approaches. Importantly, histone deacetylases (HDACs) have recently been shown to play a vital role in AF electropathology by regulating both gene transcription in the nucleus and post-translational modification of structural and contractile proteins in the leukotriene receptor agonist [[6], [7], [8]]. Importantly, small molecule inhibitors of zinc-dependent HDACs are efficacious in attenuating electropathology caused either by risk factors of AF or AF itself, and also improve contractile function in multiple pre-clinical cardiac disease models, implying a broad therapeutic applicability of HDAC inhibitors [6,7,[9], [10], [11], [12], [13], [14], [15], [16]]. HDACs catalyze removal of acetyl groups from lysine residues in numerous proteins. HDACs have mainly been studied in the context of regulation of chromatin structure, where they deacetylate nucleosomal histone tails and alter the electrostatic properties of chromatins in a manner that represses or promotes gene expression [7,17]. In addition, HDACs have many non-histone substrates, as proteomic studies have revealed that thousands of proteins undergo reversible lysine (de)acetylation [18]. Proteins that undergo (de)acetylation in the heart include cytoskeletal proteins within microtubules and cortical microfilaments (F-actin), contractile proteins within the myofibrils, Ca2+-handling proteins, RyR2 and SERCA2, and metabolism-regulating proteins, indicating that HDACs regulate calcium handling and contractile function of the heart [8,19,20]. So far, 18 mammalian HDACs have been described and they are clustered into four classes: class I HDACs (1, 2, 3 and 8), class II HDACs (4, 5, 6, 7, 9 and 10), class III HDACs (Sirtuin 1-7) and class IV (HDAC11) [4]. Class II HDACs are further separated into two subclasses, IIa (HDACs 4, 5, 7 and 9) and IIb (HDACs 6 and 10). Class I, II and IV HDACs are zinc-dependent enzymes, namely classical HDACs (Fig. 2), while class III HDACs, which are also known as Sirtuins, are NAD+ dependent enzymes [6,17]. In this review we focus on classical zinc-depend HDACs, as small molecule inhibitors of zinc-dependent HDACs are efficacious in attenuating electropathology in AF and improve contractile function in multiple pre-clinical models of cardiac diseases. Furthermore, we discuss two mechanisms by which HDACs contribute to electropathology: 1) rapid induction of post-translational modification via deacetylation of structural and contractile proteins and 2) regulation of gene expression as a long-term response. Both mechanisms may precipitate the onset and contribute to progression of cardiac diseases, especially AF (Fig. 3). Finally, we discuss the therapeutic potential of HDAC inhibition in AF.