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降低微管异化调节Nav1.5亚细胞分布,并恢复mdx心肌细胞中的电流

Giovanna Nasilli^1,2,3, Tanja M de Waal^1,2, Gerard A Marchal^1,2

¹Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Centre, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Cardiovascular research

|February 23, 2024

概括

帕瑟诺利德 (PTL) 治疗减少了杜申肌缩症 (DMD) 鼠心细胞中的微管 (MT) 异化. 这改善了电流 (INa) 和Nav1.5通道的分布,这表明MT detyrosination作为治疗点.

科学领域:

心血管生物学心血管生物学
细胞生物物理学细胞生物物理学
分子医学是分子医学.

背景情况:

微管 (MT) 网络动态对于心脏道 (Nav1.5) 贩运至关重要.
杜氏肌力发育不良 (DMD) 与增加的MT detyrosination,减少的电流 (INa) 和心律失常有关.
帕瑟诺利德 (PTL) 降低MT detyrosination,并显示在DMD中对心脏功能有希望.

研究的目的:

为了研究PTL对INa和Nav1.5在DMD中的亚细胞分布的影响.
在一个DMD模型中探索MT定化在心脏离子通道贩运中的作用.

主要方法:

来自野生型和mdx (DMD) 小鼠的心室心肌细胞被用PTL或EpoY治疗.
补丁分析评估了INa和行动潜力 (AP) 特性.
免疫光学和STORM显微镜评估了MT强化和Nav1.5集群分布.

主要成果:

MDX心肌细胞表现出增加的MT detyrosination,降低INa,并降低AP上升速度 (Vmax).
PTL治疗降低了MT detyrosination,显著增加了mdx CMs中的INA和Vmax,并在侧面膜和间隙盘中恢复了Nav1.5集群.
经过EpoY治疗,证实了MT定化与INa密度之间的直接联系.

结论:

在mdx心肌细胞中减少MT detyrosination可以恢复INa并增强Nav1.5局部化.
减少的INa在DMD中是由于双双的dystrophin缺乏和改变的Nav1.5分布二次到MT必索化.
在病理生理条件下,MT detyrosination是调节INa和Nav1.5分布的潜在治疗标.

关键词:

这是SCN5A.道贩运是道上的贸易.杜申尼肌肉发育不良症是什么离子通道的离子通道微管中的强迫性化.

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