Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS, Milano, Italy.
Cardiovasc Res. 2010 Jul 1;87(1):73-82. doi: 10.1093/cvr/cvq035. Epub 2010 Feb 17.
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.
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.
SAHA attenuates arrhythmias in mdx mice by a mechanism in which Cx remodelling and sodium channel re-expression could play an important role.
组蛋白去乙酰化酶抑制剂对营养不良性心脏功能的影响尚未确定。为了研究这一方面，用丁酸钠（SAHA，5mg/kg/天）或等量的载体处理 90 天的营养不良型 mdx 小鼠和野生型（WT）动物。
评估了以下参数：（i）静息和应激条件（束缚试验）或在乌头碱给药后室性心律失常的数量；（ii）心脏兴奋性、传导速度和不应期；（iii）连接蛋白（Cx）和 Na（v）1.5 钠通道的表达和分布。在所有静息动物中，室性心律失常都可以忽略不计。然而，在束缚期间，与 SAHA 处理的 mdx（mdx-SAHA）小鼠或正常对照（WT-V）相比，载体处理的 mdx 小鼠（mdx-V）的心律失常数量增加。有趣的是，乌头碱，一种钠离子通道药理学开放剂，在 83%的 WT-V 小鼠、11%的 mdx-V 小鼠和 57%的 mdx-SAHA 小鼠中引起室性心律失常。心外膜多导联记录显示，与 WT-V 和 WT-SAHA 小鼠相比，mdx-V 小鼠的 QRS 复合物延长，冲动传播速度显著降低。SAHA 有效地逆转了这些改变。分子分析表明，在 mdx 小鼠中，SAHA 确定了 Cx40、Cx37 和 Cx32 的 Cx 重塑，而 Cx43 和 Cx45 的表达水平没有改变。值得注意的是，SAHA 治疗逆转了 mdx 对照动物中观察到的 Cx43 侧化，同时也重新诱导了 Na（v）1.5 的表达。
SAHA 通过 Cx 重塑和钠通道重新表达的机制减轻 mdx 小鼠的心律失常，这可能发挥重要作用。
