title: Histone deacetylase inhibition reduces pulmonary vein arrhythmogenesis through calcium regulation.
abstract: Pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation (AF). Histone deacetylases (HDACs) are vital to calcium homeostasis and AF genesis. However, the electrophysiological effects of HDAC inhibition were unclear. This study evaluated whether HDAC inhibition can regulate PV electrical activity through calcium modulation. Whole-cell patch-clamp, confocal microscopic with fluorescence, and Western blot were used to evaluate electrophysiological characteristics and Ca(2+) dynamics in isolated rabbit PV cardiomyocytes with and without MPT0E014 (a pan HDAC inhibitor), MS-275 (HDAC1 and 3 inhibitor), and MC-1568 (HDAC4 and 6 inhibitor) for 5~8h. Atrial electrical activity and induced-AF (rapid atrial pacing and acetylcholine infusion) were measured in rabbits with and without MPT0E014 (10mg/kg treated for 5 hours) in vivo. MPT0E014 (1 μM)-treated PV cardiomyocytes (n=12) had slower beating rates (2.1 ± 0.2 vs. 2.8 ± 0.1 Hz, p < 0.05) than control PV cardiomyocytes. However, control (n=11) and MPT0E014 (1 μM)-treated (n = 12) SAN cardiomyocytes had similar beating rates (3.2 ± 0.2 vs. 2.9 ± 0.3 Hz). MS-275-treated PV cardiomyocytes (n = 12, 2.3 ± 0.2 Hz), but not MC-1568-treated PV cardiomyocytes (n=14, 3.1 ± 0.3 Hz) had slower beating rates than control PV cardiomocytes. MPT0E014-treated PV cardiomyocytes (n=14) had a lower frequency (2.4 ± 0.6 vs. 0.3 ± 0.1 spark/mm/s, p < 0.05) of Ca(2+) sparks than control PV (n=17) cardiomyocytes. As compared to control, MPT0E014-treated PV cardiomyocytes had reduced Ca(2+) transient amplitudes, sodium-calcium exchanger currents, and ryanodine receptor expressions. Moreover, MPT0E014-treated rabbits had less AF and shorter AF duration than control rabbits. In conclusions, HDAC inhibition reduced PV arrhythmogenesis and AF inducibility with modulation on calcium homeostasis.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Baigalmaa
authors.initials: B
authors.lastname: Lkhagva
authors.affiliation: Division of Cardiology and Cardiovascular Research Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shih-Lin
authors.initials: SL
authors.lastname: Chang
authors.affiliation: Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Kao
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yung-Kuo
authors.initials: YK
authors.lastname: Lin
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, Montreal, Canada.
authors.forename: Cindy Tzu-Hsuan
authors.initials: CT
authors.lastname: Chiu
authors.affiliation: Division of Cardiology and Cardiovascular Research Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: a9900112@ms15.hinet.net.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology* / Q000517:prevention & control*; D002118:Calcium / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D011667:Pulmonary Veins / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits
chemical_list: D056572:Histone Deacetylase Inhibitors; D002118:Calcium
keywords: Atrial fibrillation; Calcium homeostasis; Histone deacetylase inhibition; Pulmonary vein