HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment
HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment
复制标题
DOI：
10.1073/pnas.0805514105
复制
发表时间：
2008-12-09
影响因子：
11.1
通讯作者：
Gaetano, Carlo
中科院分区：
文献类型：
--
作者：
Colussi, Claudia;Mozzetta, Chiara;Gaetano, Carlo
重叠的组织学和生物化学特征，脱乙酰酶抑制剂和NO供体在营养不良的肌肉中的有益作用，表明肌营养不良蛋白，NO信号传导和组蛋白脱乙酰酶（HDAC）之间的意想不到的分子联系。在肌营养不良蛋白缺陷型MDX小鼠的肌肉中检测到更高的全局脱乙酰酶活性和I类组蛋白脱乙酰酶HDAC 2的选择性表达增加。在体外和体内siRNA介导的HDAC 2在营养不良的肌肉下调是足以复制与脱乙酰酶抑制剂和NO供体观察到的形态和功能的好处。我们发现，通过腺病毒介导的在MDX肌肉中表达组成型活性内皮NOS突变体，以及通过将MDX衍生的卫星细胞暴露于NO供体，在体内恢复NO信号传导，导致半胱氨酸S-亚硝基化的HDAC 2阻断。这些数据揭示了HDAC 2在杜氏肌营养不良症的发病机制中的特殊贡献，并表明通过NO依赖性S-亚硝基化抑制HDAC 2对于MDX小鼠中对NO供体的治疗反应是重要的。他们还定义了一个共同的目标，独立的药物干预治疗杜氏肌营养不良。
The overlapping histological and biochemical features underlying the beneficial effect of deacetylase inhibitors and NO donors in dystrophic muscles suggest an unanticipated molecular link among dystrophin, NO signaling, and the histone deacetylases (HDACs). Higher global deacetylase activity and selective increased expression of the class I histone deacetylase HDAC2 were detected in muscles of dystrophin-deficient MDX mice. In vitro and in vivo siRNA-mediated down-regulation of HDAC2 in dystrophic muscles was sufficient to replicate the morphological and functional benefits observed with deacetylase inhibitors and NO donors. We found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation. These data reveal a special contribution of HDAC2 in the pathogenesis of Duchenne muscular dystrophy and indicate that HDAC2 inhibition by NO-dependent S-nitrosylation is important for the therapeutic response to NO donors in MDX mice. They also define a common target for independent pharmacological interventions in the treatment of Duchenne muscular dystrophy.