Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ, USA.
Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ, USA.
Neuromuscul Disord. 2018 Apr;28(4):361-372. doi: 10.1016/j.nmd.2018.01.012. Epub 2018 Feb 2.
Duchenne muscular dystrophy (DMD) associated cardiomyopathy remains incurable. Connexin 43 (Cx43) is upregulated and remodeled in the hearts of mdx mice, a mouse model of DMD. Hearts from Wild Type, mdx, and mdx:Cx43(+/-) mice were studied before (4-6 months) and after (10-15 months) the onset of cardiomyopathy to assess the impact of decreasing Cx43 levels on cardiac pathology in dystrophic mice. Increased connexin 43 protein levels in mdx hearts were not observed in mdx:Cx43(+/-) hearts. Cx43 remodeling in mdx hearts was attenuated in mdx:Cx43(+/-) hearts. At time-point 4-6 months, isolated cardiomyocytes from mdx hearts displayed enhanced ethidium bromide uptake, augmented intracellular calcium signals and increased production of reactive oxygen species. These pathological features were improved in mdx:Cx43(+/-) cardiomyocytes. Isoproterenol-challenged mdx:Cx43(+/-) mice did not show arrhythmias or acute lethality observed in mdx mice. Likewise, isoproterenol-challenged mdx:Cx43(+/-) isolated hearts were also protected from arrhythmogenesis. At time-point 10-15 months, mdx:Cx43(+/-) mice showed decreased cardiac fibrosis and improved ventricular function, relative to mdx mice. These results suggest that normalization of connexin 43 protein levels in mdx mice reduces overall cardiac pathology.
杜氏肌营养不良症（DMD）相关的心肌病仍然无法治愈。连接蛋白 43（Cx43）在 DMD 模型的 mdx 小鼠的心脏中上调和重塑。研究了来自野生型、mdx 和 mdx：Cx43（+/-）小鼠的心脏，在心肌病发病前（4-6 个月）和发病后（10-15 个月）评估降低 Cx43 水平对营养不良小鼠心脏病理学的影响。在 mdx：Cx43（+/-）心脏中未观察到 mdx 心脏中 Cx43 蛋白水平的增加。mdx 心脏中的 Cx43 重塑在 mdx：Cx43（+/-）心脏中减弱。在 4-6 个月的时间点，来自 mdx 心脏的分离心肌细胞显示增强的溴化乙锭摄取、增强的细胞内钙信号和增加的活性氧产生。这些病理特征在 mdx：Cx43（+/-）心肌细胞中得到改善。异丙肾上腺素挑战的 mdx：Cx43（+/-）小鼠没有显示出 mdx 小鼠中观察到的心律失常或急性致死性。同样，异丙肾上腺素挑战的 mdx：Cx43（+/-）分离心脏也免受心律失常的发生。在 10-15 个月的时间点，与 mdx 小鼠相比，mdx：Cx43（+/-）小鼠显示出心脏纤维化减少和心室功能改善。这些结果表明，mdx 小鼠中 Cx43 蛋白水平的正常化可降低整体心脏病理学。
