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应用于心肌细胞的通道阻塞剂是否会导致通道表达增加,从而降低有效性?

Karoline Horgmo Jæger¹, Verena Charwat², Samuel Wall^3,2

¹Simula Research Laboratory, Oslo, Norway. karolihj@simula.no.

NPJ systems biology and applications

|March 1, 2024

概括

通道阻断剂 (CCB) 由于动态变化,在心脏细胞中表现出不同的疗效. 通道的升级对抗CCB的影响,影响药物反应随着时间的推移.

科学领域:

心血管药理学心血管药理学
干细胞生物学干细胞生物学
计算生物学计算生物学

背景情况:

通道阻断剂 (CCB) 在治疗心血管疾病方面至关重要.
在人类诱导的多能干细胞干细胞衍生的心肌细胞 (hiPSC-CMs) 中观察到CCB疗效的变化,特别是尼菲迪平.
在CCB效应的时间变化可能与心肌细胞内的适应机制有关.

研究的目的:

调查CCB疗效的时间变化是否与离子通道表达的适应性变化有关.
探索减少细胞内触发通道上调调节,抵消CCB效应的假设.
改进数学模型以纳入离子通道表达的动态变化.

主要方法:

利用数学模型模拟细胞内对离子通道表达的调节.
执行了hiPSC-CMs动态的时间依赖测量.
精制了肌细胞动作潜力的数学模型,包括动态离子通道数.

主要成果:

数学模型预测,CCB诱导的细胞内的减少导致离子通道表达的增加.
这种通道的上调被证明可以减弱CCBs对电流的抑制作用.
观察到的CCB疗效的变化与心脏细胞内蛋白质表达的动态变化相关.

结论:

心脏细胞的动态变化,特别是诱导蛋白质表达,可以解释CCB疗效的时间依赖变化.
了解这些适应机制对于解释基于的药物对心脏的影响至关重要.
需要仔细考虑药物应用时间,以管理CCB的疗效和细胞适应的潜在对抗作用.

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