Systemic administration of micro-dystrophin restores cardiac geometry and prevents dobutamine-induced cardiac pump failure
Systemic administration of micro-dystrophin restores cardiac geometry and prevents dobutamine-induced cardiac pump failure
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DOI：
10.1038/sj.mt.6300144
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发表时间：
2007-06-01
影响因子：
12.4
通讯作者：
Metzger, Joseph M.
中科院分区：
文献类型：
--
作者：
Townsend, DeWayne;Blankinship, Michael J.;Metzger, Joseph M.
杜氏肌营养不良症（DMD）是一种致命的疾病，横纹肌退化造成的损失的细胞骨架蛋白dystrophin。大多数患者发展为严重的心肌病，心力衰竭是DMD的第二大死亡原因。与DMD的骨骼肌缺陷和潜在治疗的广泛研究相比，很少有人关注DMD心力衰竭发病率的增加。在这里，我们表明，一个单一的全身注射的重组腺相关病毒（rAAV 2/6）窝藏micro-dystrophin导致广泛的心脏转导，与micro-dystrophin正确定位在周边的心肌细胞和功能相关的肌膜。值得注意的是，微肌养蛋白基因转移纠正了mdx小鼠心脏的基线舒张末期容积缺陷，并防止了多巴酚丁胺负荷试验诱导的心脏泵衰竭，尽管收缩功能的几个参数没有得到纠正。这些结果表明，微肌营养不良蛋白的全身基因递送可以恢复心室扩张性，并保护mdx心肌在体内肾上腺素能刺激期间免受泵功能障碍。
Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration resulting from the loss of the cytoskeletal protein dystrophin. Most patients develop significant cardiomyopathy, with heart failure being the second leading cause of death in DMD. Compared with the extensive studies on skeletal muscle defects and potential therapy in DMD, very little attention has been directed at the increasing incidence of heart failure in DMD. Here we show that a single systemic injection of recombinant adeno-associated virus (rAAV2/6) harboring micro-dystrophin leads to extensive cardiac transduction, with micro-dystrophin correctly localized at the periphery of the cardiac myocytes and functionally associated with the sarcolemmal membrane. Significantly, micro-dystrophin gene transfer corrected the baseline end-diastolic volume defect in the mdx mouse heart and prevented cardiac pump failure induced by dobutamine stress testing in vivo, although several parameters of systolic function were not corrected. These results demonstrate that systemic gene delivery of micro-dystrophin can restore ventricular distensibility and protect the mdx myocardium from pump dysfunction during adrenergic stimulation in vivo.