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Quantitative analysis of variability in an integrated model of human ventricular electrophysiology and β-adrenergic signaling.
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2020-04-21 , DOI: 10.1016/j.yjmcc.2020.04.009
Jingqi Q X Gong 1 , Monica E Susilo 2 , Anna Sher 2 , Cynthia J Musante 2 , Eric A Sobie 1
Affiliation  

In ventricular myocytes, stimulation of β-adrenergic receptors activates critical cardiac signaling pathways, leading to shorter action potentials and increased contraction strength during the "fight-or-flight" response. These changes primarily result, at the cellular level, from the coordinated phosphorylation of multiple targets by protein kinase A. Although mathematical models of the intracellular signaling downstream of β-adrenergic receptor activation have previously been described, only a limited number of studies have explored quantitative interactions between intracellular signaling and electrophysiology in human ventricular myocytes. Accordingly, our objective was to develop an integrative mathematical model of β-adrenergic receptor signaling, electrophysiology, and intracellular calcium (Ca2+) handling in the healthy human ventricular myocyte. We combined published mathematical models of intracellular signaling and electrophysiology, then calibrated the model results against voltage clamp data and physiological changes occurring after stimulation of β-adrenergic receptors with isoproterenol. We subsequently: (1) explored how molecular variability in different categories of model parameters translated into phenotypic variability; (2) identified the most important parameters determining physiological cellular outputs in the model before and after β-adrenergic receptor stimulation; and (3) investigated which molecular level alterations can produce a phenotype indicative of heart failure with preserved ejection fraction (HFpEF). Major results included: (1) variability in parameters that controlled intracellular signaling caused qualitatively different behavior than variability in parameters controlling ion transport pathways; (2) the most important model parameters determining action potential duration and intracellular Ca2+ transient amplitude were generally consistent before and after β-adrenergic receptor stimulation, except for a shift in the importance of K+ currents in determining action potential duration; and (3) decreased Ca2+ uptake into the sarcoplasmic reticulum, increased Ca2+ extrusion through Na+/Ca2+ exchanger and decreased Ca2+ leak from the sarcoplasmic reticulum may contribute to HFpEF. Overall, this study provided novel insight into the phenotypic consequences of molecular variability, and our integrated model may be useful in the design and interpretation of future experimental studies of interactions between β-adrenergic signaling and cellular physiology in human ventricular myocytes.

中文翻译:

在人类心室电生理和β-肾上腺素能信号传导综合模型中对变异性进行定量分析。

在心室肌细胞中,β-肾上腺素能受体的刺激激活了关键的心脏信号传导途径,从而导致“战斗或逃跑”反应期间的动作电位更短,收缩强度更高。这些变化主要是在细胞水平上由蛋白激酶A对多个靶标的协同磷酸化导致的。尽管先前已经描述了β-肾上腺素能受体激活下游的细胞内信号传导的数学模型,但仅有限数量的研究进行了定量研究。人心室肌细胞中细胞内信号传导与电生理之间的相互作用。因此,我们的目标是建立一个β-肾上腺素受体信号传导,电生理学,和健康人心室肌细胞中的细胞内钙(Ca2 +)处理。我们结合了已发表的细胞内信号传导和电生理学数学模型,然后针对电压钳数据和异丙肾上腺素刺激β-肾上腺素受体后发生的生理变化对模型结果进行了校准。随后我们:(1)探索了不同类别的模型参数中的分子变异性如何转化为表型变异性;(2)确定了确定模型中β-肾上腺素受体刺激前后生理细胞输出的最重要参数;(3)研究了哪些分子水平的改变可以产生表型,表明心力衰竭的射血分数(HFpEF)保持不变。主要结果包括:(1)控制细胞内信号转导的参数变化与控制离子传输途径的参数变化在性质上有不同的行为;(2)在确定β-肾上腺素能受体刺激前后,最重要的确定动作电位持续时间和细胞内Ca2 +瞬变幅度的模型参数基本一致,除了K +电流在决定动作电位持续时间方面的重要性发生了变化外;(3)减少的Ca2 +吸收进入肌浆网,通过Na + / Ca2 +交换体增加的Ca2 +挤出和肌浆网中Ca2 +的泄漏减少可能是HFpEF的原因。总体而言,这项研究为分子变异的表型后果提供了新颖的见解,
更新日期:2020-04-22
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