Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice
Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice
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DOI：
10.1093/hmg/ddl151
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发表时间：
2006-07-15
影响因子：
3.5
通讯作者：
Miike, Teruhisa
中科院分区：
文献类型：
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作者：
Ito, Kaori;Kimura, Shigemi;Miike, Teruhisa
Duchenne肌营养不良症(DMD)是一种致命的X连锁肌肉萎缩疾病，由编码细胞骨架蛋白dystrophin的基因突变引起。DMD的治疗选择是有限的，因为Dstrophin缺乏导致临床表型的发病机制仍然不清楚。最近关于DMD患者运动肌肉和DMD动物模型MDX小鼠运动肌肉中α-肾上腺素能血管调节异常的报道，促使我们假设Dstrophin缺乏的平滑肌与DMD的血管和营养不良表型有关。为了测试这一点，我们产生了只在平滑肌(SMTg/MDX)表达dystrophin的转基因MDX小鼠。我们发现，在C57BL/10野生型小鼠的后肢收缩中，α-肾上腺素能血管收缩明显减弱，这一作用是由一氧化氮(NO)介导的，而在MDX小鼠中则受到严重损害。SMTg/MDX小鼠表现出中等表型，部分恢复了活跃肌肉中对α-肾上腺素能血管收缩的NO依赖调节。此外，在mdx小鼠中观察到的升高的血清肌酸激酶水平在SMTg/mdx小鼠中显著降低。这是第一次关于肌营养不良蛋白在血管平滑肌中的功能作用的报道。
Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disease caused by mutations of the gene encoding the cytoskeletal protein dystrophin. Therapeutic options for DMD are limited because the pathogenetic mechanism by which dystrophin deficiency produces the clinical phenotype remains obscure. Recent reports of abnormal alpha-adrenergic vasoregulation in the exercising muscles of DMD patients and in the mdx mouse, an animal model of DMD, prompted us to hypothesize that the dystrophin-deficient smooth muscle contributes to the vascular and dystrophic phenotypes of DMD. To test this, we generated transgenic mdx mice that express dystrophin only in smooth muscle (SMTg/mdx). We found that alpha-adrenergic vasoconstriction was markedly attenuated in the contracting hindlimbs of C57BL/10 wild-type mice, an effect that was mediated by nitric oxide (NO) and was severely impaired in the mdx mice. SMTg/mdx mice showed an intermediate phenotype, with partial restoration of the NO-dependent modulation of alpha-adrenergic vasoconstriction in active muscle. In addition, the elevated serum creatine kinase levels observed in mdx mice were significantly reduced in SMTg/mdx mice. This is the first report of a functional role of dystrophin in vascular smooth muscle.