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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