Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States of America.
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
J Mol Cell Cardiol. 2023 Jan;174:1-14. doi: 10.1016/j.yjmcc.2022.10.006. Epub 2022 Nov 10.
Familial cardiomyopathy is a precursor of heart failure and sudden cardiac death. Over the past several decades, researchers have discovered numerous gene mutations primarily in sarcomeric and cytoskeletal proteins causing two different disease phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathies. However, molecular mechanisms linking genotype to phenotype remain unclear. Here, we employ a systems approach by integrating experimental findings from preclinical studies (e.g., murine data) into a cohesive signaling network to scrutinize genotype to phenotype mechanisms. We developed an HCM/DCM signaling network model utilizing a logic-based differential equations approach and evaluated model performance in predicting experimental data from four contexts (HCM, DCM, pressure overload, and volume overload). The model has an overall prediction accuracy of 83.8%, with higher accuracy in the HCM context (90%) than DCM (75%). Global sensitivity analysis identifies key signaling reactions, with calcium-mediated myofilament force development and calcium-calmodulin kinase signaling ranking the highest. A structural revision analysis indicates potential missing interactions that primarily control calcium regulatory proteins, increasing model prediction accuracy. Combination pharmacotherapy analysis suggests that downregulation of signaling components such as calcium, titin and its associated proteins, growth factor receptors, ERK1/2, and PI3K-AKT could inhibit myocyte growth in HCM. In experiments with patient-specific iPSC-derived cardiomyocytes (MLP-W4R;MYH7-R723C iPSC-CMs), combined inhibition of ERK1/2 and PI3K-AKT rescued the HCM phenotype, as predicted by the model. In DCM, PI3K-AKT-NFAT downregulation combined with upregulation of Ras/ERK1/2 or titin or Gq protein could ameliorate cardiomyocyte morphology. The model results suggest that HCM mutations that increase active force through elevated calcium sensitivity could increase ERK activity and decrease eccentricity through parallel growth factors, Gq-mediated, and titin pathways. Moreover, the model simulated the influence of existing medications on cardiac growth in HCM and DCM contexts. This HCM/DCM signaling model demonstrates utility in investigating genotype to phenotype mechanisms in familial cardiomyopathy.
家族性心肌病是心力衰竭和心源性猝死的前兆。在过去的几十年中，研究人员发现了许多主要在肌节和细胞骨架蛋白中的基因突变，导致两种不同的疾病表型：肥厚型（HCM）和扩张型（DCM）心肌病。然而，基因型与表型之间的分子机制仍不清楚。在这里，我们通过将临床前研究（例如，鼠类数据）的实验结果整合到一个有凝聚力的信号网络中，采用系统方法来研究基因型与表型的机制。我们利用基于逻辑的微分方程方法开发了一种 HCM/DCM 信号网络模型，并评估了该模型在预测来自四个环境（HCM、DCM、压力超负荷和容量超负荷）的实验数据方面的性能。该模型的总体预测准确率为 83.8%，在 HCM 环境下的准确率（90%）高于 DCM（75%）。全局敏感性分析确定了关键的信号反应，其中钙介导的肌丝力发展和钙调蛋白激酶信号排名最高。结构修正分析表明潜在的缺失相互作用主要控制钙调节蛋白，从而提高模型预测的准确性。组合药物治疗分析表明，下调信号成分，如钙、肌联蛋白及其相关蛋白、生长因子受体、ERK1/2 和 PI3K-AKT，可能抑制 HCM 中的心肌细胞生长。在具有患者特异性 iPSC 衍生的心肌细胞（MLP-W4R；MYH7-R723C iPSC-CMs）的实验中，如模型预测的那样，联合抑制 ERK1/2 和 PI3K-AKT 可挽救 HCM 表型。在 DCM 中，下调 PI3K-AKT-NFAT 与上调 Ras/ERK1/2 或肌联蛋白或 Gq 蛋白相结合，可改善心肌细胞形态。模型结果表明，通过增加钙敏感性增加主动力的 HCM 突变可能通过平行的生长因子、Gq 介导的和肌联蛋白途径增加 ERK 活性并降低离心率。此外，该模型模拟了现有药物对 HCM 和 DCM 环境中心脏生长的影响。该 HCM/DCM 信号模型证明了在研究家族性心肌病的基因型与表型机制方面的实用性。
