Tan Philip M, Buchholz Kyle S, Omens Jeffrey H, McCulloch Andrew D, Saucerman Jeffrey J
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America.
Departments of Bioengineering and Medicine, University of California San Diego, La Jolla, California, United States of America.
PLoS Comput Biol. 2017 Nov 13;13(11):e1005854. doi: 10.1371/journal.pcbi.1005854. eCollection 2017 Nov.
Mechanical strain is a potent stimulus for growth and remodeling in cells. Although many pathways have been implicated in stretch-induced remodeling, the control structures by which signals from distinct mechano-sensors are integrated to modulate hypertrophy and gene expression in cardiomyocytes remain unclear. Here, we constructed and validated a predictive computational model of the cardiac mechano-signaling network in order to elucidate the mechanisms underlying signal integration. The model identifies calcium, actin, Ras, Raf1, PI3K, and JAK as key regulators of cardiac mechano-signaling and characterizes crosstalk logic imparting differential control of transcription by AT1R, integrins, and calcium channels. We find that while these regulators maintain mostly independent control over distinct groups of transcription factors, synergy between multiple pathways is necessary to activate all the transcription factors necessary for gene transcription and hypertrophy. We also identify a PKG-dependent mechanism by which valsartan/sacubitril, a combination drug recently approved for treating heart failure, inhibits stretch-induced hypertrophy, and predict further efficacious pairs of drug targets in the network through a network-wide combinatorial search.
机械应变是细胞生长和重塑的有力刺激因素。尽管许多信号通路都与拉伸诱导的重塑有关，但不同机械传感器发出的信号整合以调节心肌细胞肥大和基因表达的控制结构仍不清楚。在此，我们构建并验证了心脏机械信号网络的预测计算模型，以阐明信号整合的潜在机制。该模型确定钙、肌动蛋白、Ras、Raf1、PI3K和JAK为心脏机械信号的关键调节因子，并表征了赋予AT1R、整合素和钙通道对转录进行差异控制的串扰逻辑。我们发现，虽然这些调节因子对不同组的转录因子大多保持独立控制，但多条信号通路之间的协同作用对于激活基因转录和肥大所需的所有转录因子是必要的。我们还确定了一种PKG依赖性机制，最近被批准用于治疗心力衰竭的复方药物缬沙坦/沙库巴曲通过该机制抑制拉伸诱导的肥大，并通过全网络组合搜索预测网络中其他有效的药物靶点对。
