title: Activation of histone deacetylase-6 induces contractile dysfunction through derailment of α-tubulin proteostasis in experimental and human atrial fibrillation.
abstract: BACKGROUND
  Atrial fibrillation (AF) is characterized by structural remodeling, contractile dysfunction, and AF progression. Histone deacetylases (HDACs) influence acetylation of both histones and cytosolic proteins, thereby mediating epigenetic regulation and influencing cell proteostasis. Because the exact function of HDACs in AF is unknown, we investigated their role in experimental and clinical AF models.
  
  
  RESULTS
  Tachypacing of HL-1 atrial cardiomyocytes and Drosophila pupae hearts significantly impaired contractile function (amplitude of Ca(2+) transients and heart wall contractions). This dysfunction was prevented by inhibition of HDAC6 (tubacin) and sirtuins (nicotinamide). Tachypacing induced specific activation of HDAC6, resulting in α-tubulin deacetylation, depolymerization, and degradation by calpain. Tachypacing-induced contractile dysfunction was completely rescued by dominant-negative HDAC6 mutants with loss of deacetylase activity in the second catalytic domain, which bears α-tubulin deacetylase activity. Furthermore, in vivo treatment with the HDAC6 inhibitor tubastatin A protected atrial tachypaced dogs from electric remodeling (action potential duration shortening, L-type Ca(2+) current reduction, AF promotion) and cellular Ca(2+)-handling/contractile dysfunction (loss of Ca(2+) transient amplitude, sarcomere contractility). Finally, atrial tissue from patients with AF also showed a significant increase in HDAC6 activity and reduction in the expression of both acetylated and total α-tubulin.
  
  
  CONCLUSIONS
  AF induces remodeling and loss of contractile function, at least in part through HDAC6 activation and subsequent derailment of α-tubulin proteostasis and disruption of the cardiomyocyte microtubule structure. In vivo inhibition of HDAC6 protects against AF-related atrial remodeling, disclosing the potential of HDAC6 as a therapeutic target in clinical AF.
authors.affiliation: Departments of Clinical Pharmacology (D.Z., R.A.M.M., F.H.-B., R.H.H., B.J.J.M.B.) and Cell Biology (O.C.M.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Research Center and Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QB, Canada (C.T.W., X.Y.Q., A.T., S.N.); Chang-Gung Memorial Hospital and Chang-Gung University, Taoyuan, Taiwan, Republic of China (C.T.W.); Nyken BV, Groningen, The Netherlands (F.-H.B.); Ankara University Biotechnology Institute, Ankara, Turkey (G.C.D., S.D.); Ankara University Stem Cell Institute, Ankara, Turkey (G.C.D., S.D., A.R.A.); Department of Cardiovascular Surgery, Ankara University School of Medicine, Ankara, Turkey (S.D., A.R.A.); and Department of Pharmacology, McGill University, Montreal, QB, Canada (S.N.).
authors.forename: Deli
authors.initials: D
authors.lastname: Zhang
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Wu
authors.forename: XiaoYan
authors.initials: X
authors.lastname: Qi
authors.forename: Roelien A M
authors.initials: RA
authors.lastname: Meijering
authors.forename: Femke
authors.initials: F
authors.lastname: Hoogstra-Berends
authors.forename: Artavazd
authors.initials: A
authors.lastname: Tadevosyan
authors.forename: Gunseli
authors.initials: G
authors.lastname: Cubukcuoglu Deniz
authors.forename: Serkan
authors.initials: S
authors.lastname: Durdu
authors.forename: Ahmet Ruchan
authors.initials: AR
authors.lastname: Akar
authors.forename: Ody C M
authors.initials: OC
authors.lastname: Sibon
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
authors.forename: Bianca J J M
authors.initials: BJ
authors.lastname: Brundel
mesh_terms: D000107:Acetylation; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000503:physiopathology; D064752:Atrial Remodeling / Q000502:physiology; D002154:Calpain / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004330:Drosophila; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology*; D014404:Tubulin / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D006877:Hydroxamic Acids; D007211:Indoles; D014404:Tubulin; C553587:tubastatin A; D002154:Calpain; C425683:HDAC6 protein, Drosophila; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Drosophila; HDAC6 protein, Drosophila; HDAC6 protein, human; alpha-tubulin deacetylase; atrial fibrillation; epigenesis, genetic