The histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces cardiac arrhythmias in dystrophic mice.
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.
Colussi
Claudia
C
Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS, Milano, Italy.
Berni
Roberta
R
Rosati
Jessica
J
Straino
Stefania
S
Vitale
Serena
S
Spallotta
Francesco
F
Baruffi
Silvana
S
Bocchi
Leonardo
L
Delucchi
Francesca
F
Rossi
Stefano
S
Savi
Monia
M
Rotili
Dante
D
Quaini
Federico
F
Macchi
Emilio
E
Stilli
Donatella
D
Musso
Ezio
E
Mai
Antonello
A
Gaetano
Carlo
C
Capogrossi
Maurizio C
MC
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
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