Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium
Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium
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DOI：
10.1093/hmg/ddi197
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发表时间：
2005-07-15
影响因子：
3.5
通讯作者：
Tidball, JG
中科院分区：
文献类型：
--
作者：
Wehling-Henricks, M;Jordan, MC;Tidball, JG
肌营养不良蛋白的突变导致杜氏肌营养不良症（DMD）的致命病理，其中存在骨骼肌和心肌的进行性病理。尽管肌营养不良蛋白突变与心脏缺陷之间的关系尚不清楚，但大部分DMD患者的死亡可归因于与心室纤维化、心律失常和传导异常相关的心功能障碍。在这里，我们测试了是否可以通过心肌产生一氧化氮（NO）的升高来纠正肌营养不良蛋白缺陷mdx小鼠的心脏病理。产生肌营养不良蛋白缺陷mdx小鼠，其中存在神经元型一氧化氮合酶（nNOS）转基因的心肌表达。转基因的表达阻止了mdx小鼠进行性心室纤维化，并大大减少了心肌炎。通过无线电遥测获得的自由行走小鼠的心电图（ECG）显示，mdx小鼠显示出DMD患者特有的心脏异常，包括深Q波、S：R比降低、多相R波和频繁的室性早搏。mdx小鼠的所有这些ECG异常均通过nNOS转基因表达得到改善或纠正。此外，mdx心脏自主神经功能的缺陷，这反映了降低心率变异性，显着减少nNOS转基因表达。这些发现表明，增加NO生产营养不良的心脏可能具有治疗价值。
Null mutation of dystrophin causes the lethal pathology of Duchenne muscular dystrophy (DMD) in which there is progressive pathology of skeletal and cardiac muscles. A large proportion of DMD patient deaths are attributable to cardiac dysfunction associated with ventricular fibrosis, arrhythmias and conduction abnormalities, although the relationships between the dystrophin mutation and the cardiac defects are unknown. Here, we tested whether cardiac pathology in dystrophin-deficient mdx mice can be corrected by the elevated production of nitric oxide (NO) by the myocardium. Dystrophin-deficient mdx mice were produced in which there was myocardial expression of a neuronal nitric oxide synthase (nNOS) transgene. Expression of the transgene prevented the progressive ventricular fibrosis of mdx mice and greatly reduced myocarditis. Electrocardiographs (ECG) attained by radiotelemetry of freely ambulatory mice showed that mdx mice displayed cardiac abnormalities that are characteristic of DMD patients, including deep Q-waves, diminished S:R ratios, polyphasic R-waves and frequent premature ventricular contractions. All of these ECG abnormalities in mdx mice were improved or corrected by nNOS transgene expression. In addition, defects in mdx cardiac autonomic function, which were reflected by decreased heart rate variability, were significantly reduced by nNOS transgene expression. These findings indicate that increasing NO production by dystrophic hearts may have therapeutic value.