Modeling the Interplay of Sex Hormones in Cardiac Hypertrophic Signaling

Abstract

Biological sex plays a crucial role in the outcomes of cardiac health and therapies. Sex hormones are known to strongly influence cardiac remodeling through intracellular signaling pathways, yet their underlying mechanisms remain unclear. To address this need, we developed and validated a logic-based systems biology model of cardiomyocyte hypertrophy that, for the first time, incorporates the effects of both estradiol (E2) and testosterone (T) alongside well-established hypertrophic stimuli (Strain, angiotensin II (AngII), and endothelin-1 (ET-1)). We qualitatively validated the model to literature data with 84% agreement. Quantitative validation was done by simulating the impact of the inputs (E2, T, Strain, AngII, and ET-1) on cardiac hypertrophy, captured as change in CellArea. We perturbed the validated model to examine the differential response to hypertrophy and identify changes in influential and sensitive downstream nodes for a male, pre-menopausal female, and post-menopausal female condition. Our results suggest that T has a greater impact on hypertrophy than E2. This model increases our understanding of the mechanisms through which sex hormones influence cardiac hypertrophy and can aid with developing more effective cardiac therapies for all patients. Author summaryDifferences between female and male hearts extend far beyond size and structure. Sex hormones estradiol and testosterone play key roles in sex-specific cardiac remodeling via intracellular pathways. Understanding how these sex hormones impact cardiac remodeling is critical for developing more effective, sex-specific approaches to cardiovascular care. Logic-based systems biology models have proven useful in quantifying and analyzing complex and intricate intracellular signaling network dynamics in various cell types. We leverage this method to develop a model of cardiomyocyte hypertrophy, which, for the first time, includes the effect of both estradiol and testosterone. Considering the combined influence of these hormones is important because both women and men have varying concentrations of these hormones throughout their lives. The model was developed and validated based on previously published studies. We then investigated differences in cardiomyocyte hypertrophy in pre- and post-menopausal women and men.