Computational Screen for Sex-Specific Drug Effects in a Cardiac Fibroblast Network Model

Heart disease is the leading cause of death in both men and women. Cardiac fibrosis is the uncontrolled accumulation of extracellular matrix proteins which can exacerbate the progression of heart failure, and there are currently no drugs approved specifically to target matrix accumulation in the heart. Computational signaling network models (SNMs) can be used to facilitate discovery of novel drug targets. However, the vast majority of SNMs are not sex-specific and/or are developed and validated using data skewed towards male in vitro and in vivo samples. Biological sex is an important consideration in cardiovascular health and drug development. In this study, we integrate a previously constructed cardiac fibroblast SNM with estrogen signaling pathways to create sex-specific SNMs. The sex-specific SNMs maintained previously high validation when compared to in vitro experimental studies in the literature. A sex-specific perturbation analysis and drug screen uncovered several potential pathways that warrant further study in the pursuit of sex-specific treatment recommendations for cardiac fibrosis. Author Summary Heart failure is a leading cause of death for both men and women, but we still do not have adequate therapies to prevent or reverse this disease. One factor that contributes to heart failure is scarring of cardiac tissue, also known as fibrosis. Computer models can help find new heart failure drugs by simulating hundreds of biological reactions that regulate fibrosis at the molecular level. Unfortunately, the differences in male and female patients are not usually considered for these drug discovery simulations, which can result in drugs that work well for some individuals but not for other individuals. In our study, we added sex-specific biological reactions to a computer model in order to identify drugs that could treat fibrosis differently in male and female patients. Our simulations also predicted why premenopausal women may generally develop less fibrosis than men, while post-menopausal women may develop similar levels of fibrosis as men.