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 82% 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 pre-menopausal female, post-menopausal female, younger male, and older male condition. Our model shows how T and E2 interact with each other and other hypertrophic stimuli, with T demonstrating a more potent hypertrophic effect 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.