Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Early Clinical Development, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA.
J Mol Cell Cardiol. 2020 Jun;143:96-106. doi: 10.1016/j.yjmcc.2020.04.009. Epub 2020 Apr 21.
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 (Ca) 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 Ca 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 Ca uptake into the sarcoplasmic reticulum, increased Ca extrusion through Na/Ca exchanger and decreased Ca 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.
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通路，导致在“战斗或逃跑”反应期间动作电位缩短和收缩强度增加。这些变化主要是由于蛋白激酶 A 对多个靶标的协调磷酸化，在细胞水平上产生的。尽管之前已经描述了β-肾上腺素能受体激活下游的细胞内信号的数学模型，但只有少数研究探索了人类心室肌细胞中细胞内信号与电生理学之间的定量相互作用。因此，我们的目标是开发一种健康人类心室肌细胞中β-肾上腺素能受体信号、电生理学和细胞内钙（Ca）处理的综合数学模型。我们结合了已发表的细胞内信号和电生理学数学模型，然后根据电压钳数据和异丙肾上腺素刺激β-肾上腺素能受体后发生的生理变化对模型结果进行校准。随后，我们：（1）探讨了模型参数不同类别的分子变异性如何转化为表型变异性；（2）确定了β-肾上腺素能受体刺激前后模型中决定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心力衰竭伴射血分数保留（HFpEF）的表型。主要结果包括：（1）控制细胞内信号的参数的变异性引起的行为与控制离子转运途径的参数的变异性有质的不同；（2）决定动作电位持续时间和细胞内 Ca 瞬变幅度的最重要模型参数在β-肾上腺素能受体刺激前后通常是一致的，除了 K 电流在决定动作电位持续时间方面的重要性发生变化；（3）肌浆网 Ca 摄取减少、Na/Ca 交换器的 Ca 外排增加和肌浆网 Ca 泄漏减少可能导致 HFpEF。总体而言，这项研究提供了分子变异性对表型影响的新见解，我们的综合模型可能有助于设计和解释未来关于β-肾上腺素能信号与人类心室肌细胞细胞生理学之间相互作用的实验研究。
