title: The histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces cardiac arrhythmias in dystrophic mice.
abstract: OBJECTIVE
  The effect of histone deacetylase inhibitors on dystrophic heart function is not established. To investigate this aspect, dystrophic mdx mice and wild-type (WT) animals were treated 90 days either with suberoylanilide hydroxamic acid (SAHA, 5 mg/kg/day) or with an equivalent amount of vehicle.
  
  
  RESULTS
  The following parameters were evaluated: (i) number of ventricular arrhythmias in resting and stress conditions (restraint test) or after aconitine administration; (ii) cardiac excitability, conduction velocity, and refractoriness; (iii) expression and distribution of connexins (Cxs) and Na(v)1.5 sodium channel. Ventricular arrhythmias were negligible in all resting animals. During restraint, however, an increase in the number of arrhythmias was detected in vehicle-treated mdx mice (mdx-V) when compared with SAHA-treated mdx (mdx-SAHA) mice or normal control (WT-V). Interestingly, aconitine, a sodium channel pharmacologic opener, induced ventricular arrhythmias in 83% of WT-V mice, 11% of mdx-V, and in 57% of mdx-SAHA. Epicardial multiple lead recording revealed a prolongation of the QRS complex in mdx-V mice in comparison to WT-V and WT-SAHA mice, paralleled by a significant reduction in impulse propagation velocity. These alterations were efficiently counteracted by SAHA. Molecular analyses revealed that in mdx mice, SAHA determined Cx remodelling of Cx40, Cx37 and Cx32, whereas expression levels of Cx43 and Cx45 were unaltered. Remarkably, Cx43 lateralization observed in mdx control animals was reversed by SAHA treatment which also re-induced Na(v)1.5 expression.
  
  
  CONCLUSIONS
  SAHA attenuates arrhythmias in mdx mice by a mechanism in which Cx remodelling and sodium channel re-expression could play an important role.
authors.affiliation: Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Colussi
authors.forename: Roberta
authors.initials: R
authors.lastname: Berni
authors.forename: Jessica
authors.initials: J
authors.lastname: Rosati
authors.forename: Stefania
authors.initials: S
authors.lastname: Straino
authors.forename: Serena
authors.initials: S
authors.lastname: Vitale
authors.forename: Francesco
authors.initials: F
authors.lastname: Spallotta
authors.forename: Silvana
authors.initials: S
authors.lastname: Baruffi
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bocchi
authors.forename: Francesca
authors.initials: F
authors.lastname: Delucchi
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossi
authors.forename: Monia
authors.initials: M
authors.lastname: Savi
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Federico
authors.initials: F
authors.lastname: Quaini
authors.forename: Emilio
authors.initials: E
authors.lastname: Macchi
authors.forename: Donatella
authors.initials: D
authors.lastname: Stilli
authors.forename: Ezio
authors.initials: E
authors.lastname: Musso
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
mesh_terms: D000157:Aconitine; D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D017630:Connexins / Q000378:metabolism; D004195:Disease Models, Animal; D015716:Electrocardiography, Ambulatory; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012149:Restraint, Physical; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013686:Telemetry; D013997:Time Factors; D000077337:Vorinostat
chemical_list: D000889:Anti-Arrhythmia Agents; D017630:Connexins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D000077337:Vorinostat; D000157:Aconitine