Histone Deacetylase Inhibition Reduces Pulmonary Vein Arrhythmogenesis through Calcium Regulation
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia seen in clinical practice, and contributes to morbidity and mortality in the general population [1]. However, the pathophysiology underlying AF is not fully elucidated, and the current treatment of AF is unsatisfactory [2], [3]. Histone deacetylases (HDACs), which are epigenetic regulators, play critical roles in altering gene expressions during the progression of remodeling processes of cardiovascular diseases [4]. Reversible acetylation of histone and non-histone nuclear and cytosolic proteins was implicated in multiple cellular regulatory processes of cardiovascular diseases [5]. HDAC inhibitors can reduce cardiac hypertrophy and fibrosis [4], [6], [7], [8]. Our previous study has shown that a novel pan HDAC inhibitor (3-(1-Benzenesulfonyl-1H-indol-5-yl)-N-hydroxyacrylamide, MPT0E014) can improve heart failure with modulation on calcium regulation proteins [6]. Moreover, HDAC inhibitors were also shown to reduce AF induction in genetically modified mice with increased HDAC activity [9]. Activation of HDAC6 can enhance the occurrence of AF with contractile dysfunction, and AF patients had increased HDAC6 activities [10]. These findings suggest the potential role of inhibiting HDACs to treat AF. However, knowledge of the electrophysiological effects and calcium regulatory mechanisms of HDAC inhibition is limited.
Pulmonary veins (PVs), are the most important ectopic foci for AF initiation [11], [12]. PV cardiomyocytes contain distinctive electrophysiological characteristics with abnormally triggered activities [12], [13]. PV cardiomyocytes have increased sarcoplasmic reticulum (SR) Ca2 + stores and Ca2 + sparks [13], which suggests that calcium dysregulation may lead to PV arrhythmogenesis. Enhanced calmodulin-dependent protein kinase II (CaMKII) and the phosphorylated ryanodine receptor (RyR) can enhance calcium leak which produces calcium sparks and generates triggered activity [14]. In addition, increased sodium calcium exchanger (NCX) currents and CaMKII-hyperphosphorylated RyR were demonstrated in AF patients [15]. Modulating PV calcium homeostasis controls PV electrical activity, which may reduce the risk of AF [16], [17], [18]. In contrast, sinoatrial node (SAN) dysfunction may enhance the occurrences of AF [19]. HDACs and HDAC inhibitors can modulate expressions of calcium regulatory proteins [20], [21]. Therefore, the purpose of this study was to examine whether HDAC inhibition can modulate PV or SAN electrical activity through calcium modulation.
Section snippets
Isolation of PV and SAN cardiomyocytes
The investigation was approved by a local ethics review board and was conducted in accordance with the US National Institute of Health’s Guide for the Care and Use of Laboratory Animals. Male rabbits (1.5 ~ 2 kg) were intravenously injected with sodium pentobarbital (100 mg⁄kg) and heparin (2500 units). Single cardiomyocytes from rabbit PVs and SANs were enzymatically dissociated by a previously described procedure [22]. Cardiomyocytes with spontaneous activity were identified by the presence of
Effects of MPT0E014 on PV APs, electrical activity, and calcium homeostasis
As shown in Fig. 1, MPT0E014-treated PV cardiomyocytes had a slower beating rate than control PV cardiomyocytes (2.1 ± 0.2 vs. 2.8 ± 0.1 Hz, p < 0.05) at the concentration of 1 μM, but not at 0.1 μM (Fig. 1A). However, control and MPT0E014-treated (0.1 and 1 μM) SAN cardiomyocytes had similar beating rates (3.2 ± 0.2 vs. 2.9 ± 0.3 Hz) (Fig. 1B). Moreover, MS-275(1 μM)-treated PV cardiomyocytes had a slower beating rate (n = 12, 2.3 ± 0.2 Hz) than control or MC-1568 (1 μM)-treated PV cardiomyocytes (n = 14, 3.1 ± 0.3 Hz) (
Discussion
In the present study, for the first time, we showed that an HDAC inhibitor may contain anti-AF potential through modulating calcium regulation in PV cardiomyocytes. Increased HDAC activity can produce atrial fibrosis and atrial arrhythmic susceptibility in transgenic mice. Although pharmacologic inhibition of HDAC suppressed atrial fibrosis and atrial arrhythmia [9], the effects of HDAC inhibition on ion channels, calcium homeostasis, and arrhythmogenesis were not assessed [9], [27]. We found
Disclosures
The authors declare no conflict of interest.
Acknowledgements
The present work was supported by grants from Taipei Medical University, Wan Fang Hospital (103swf-10, 103-wf-eva-02 and 102-wf-eva-01), and the Ministry of Science and Technology, Taiwan (MOST 100-2628-B-038-001-MY4, 102-2628-B-038-002-MY3, and 102-2325-B-010-005).
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2021, Life SciencesCitation Excerpt :Pan-HDAC inhibition by TSA or SAHA produces dose-dependent reductions in Gja1 transcription in ventricular cardiomyocytes [26]. Preclinical studies in murine models revealed positive effects of HDAC inhibition by small-molecule compounds [11,27,28] on atrial fibrillation, and recent data from humans and murine cardiomyocytes showed electrophysiological effects suggesting regulation of K+ channel expression [16,17,27,29]. Global inhibition of class I or class II HDACs result in rather broad and partially unspecific effects on ion channel expression and changes of cardiac electrophysiology.
Functional genomics and epigenomics of atrial fibrillation
2021, Journal of Molecular and Cellular CardiologyCitation Excerpt :An additional well-known example applies to histone deacetylases (HDACs) that act as proteostasis regulators in AF, by removing acetyl groups from the lysine residues of nucleosomal histone tails and various non-histone proteins. HDAC inhibition reverses atrial fibrosis and arrhythmogenesis and restore expression levels of Connexin40 in mice [117], and also in rabbit cardiomyocytes by modulating calcium homeostasis [118]. HDACs modulate the expression of relevant cardiac transcription factors such as MEF2 [119], which has a role in hypertrophy and fibrosis.
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2018, Translational ResearchCitation Excerpt :HDAC inhibitors are known to reduce proinflammatory cytokines and attenuate inflammation and oxidative stress,31 which may contribute to the lower incidence of frequent APCs in MPT0E014-treated op rabbits and a lower incidence of burst firings in MPT0E014-treated opPVs. Our previous study showed that MPT0E014 decreased the sodium-calcium exchanger current and calcium transient.32,33 This calcium-regulatory effect could result in slower spontaneous activity in MPT0E014-treated control PVs or opPVs.
Targeting histone deacetylases: A novel therapeutic strategy for atrial fibrillation
2016, European Journal of PharmacologyCitation Excerpt :MS-275 (which selectively inhibits HDAC1, -2, and -3), but not MC-1568 (which selectively inhibits class II HDACs), showed similar effects as MPT0E014 on PV cardiomyocytes. These findings suggest that class I HDAC inhibition is more likely to contribute to anti-AF potential through PV regulation (Lkhagva et al., 2014). Table 1 summarizes the experimental evidence supporting the potential anti-AF effects of HDAC inhibition via electrical or structural remodeling.
Epigenetic mechanisms in atrial fibrillation: New insights and future directions
2016, Trends in Cardiovascular MedicineCitation Excerpt :As compared to control, MPT0E014-treated PV cardiomyocytes had reduced Ca(2+) transient amplitudes, sodium-calcium exchanger currents, and ryanodine receptor expressions [80]. Moreover, MPT0E014-treated rabbits had less AF and shorter AF duration than control rabbits [80]. In conclusions, HDAC inhibition reduced PV arrhythmogenesis and AF inducibility with modulation on calcium homeostasis.