Using a Computational Model of Cardiac Fibroblast Signaling to Screen for Drugs Effective Against Heart Failure

Cardiac fibroblasts are the cells responsible for remodeling the heart’s extracellular matrix (ECM) after a myocardial infarction. ECM breakdown during the early, inflammatory phase of remodeling should be balanced with deposition of new collagen during the proliferative phase in order to maintain cardiac function and prevent heart failure. Currently, it is not clear which drug(s) would best modulate ECM production by fibroblasts because relevant proteins and signaling pathways are typically studied in isolation. In this study, we adopted a systems biology approach to perform a comprehensive drug screen using a fibroblast signaling network that integrated 10 signaling pathways with 104 molecules and 157 reactions. We developed a differential equation model for the reactions in the network and used the DrugBank database to obtain information on 114 FDA approved/investigational drugs that had a target within our network. We simulated the addition of each drug to the model in either the proliferative or inflammatory phases and observed the foldchange in activity of 8 network outputs, including collagen I and III protein. Drugs such as Arbutamine, Amyl Nitrate and Arsenic Trioxide were predicted to decrease collagen levels during the proliferative phase, thereby potentially helping prevent excess ECM deposition. Siltuximab and Triflusal were predicted to increase collagen protein during the inflammatory phase, thereby working to prevent excess ECM degradation.