Aims 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, 5mg/kg/day) or equivalent amount of vehicle. Methods and Results The following parameters were evaluated: 1) number of ventricular arrhythmias in resting and stress conditions (restraint test) or after Aconitine administration; 2) cardiac excitability, conduction velocity, and refractoriness; 3) expression and distribution of connexins and Nav1.5 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) as compared to SAHA treated mdx (mdx-SAHA) mice or normal control (WT-V respectively). Interestingly, Aconitine, a sodium channel pharmacologic opener, induced ventricular arrhythmias in 83% of WT-V mice, 11% of mdx-V and in the 57% of mdx-SAHA. Epicardial multiple lead recording revealed a prolongation of 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 connexion (Cx) remodelling of Cx40, Cx37 and Cx32, while 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 Nav1.5 expression. Conclusion SAHA attenuates arrhythmias in mdx mice by a mechanism in which Cx remodelling and sodium channel re-expression could play an important role.
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