BPS2026 – Computational modeling identifies protective mechanisms of estrogen and testosterone against atrial fibrosis

Atrial fibrillation (AF), the most common sustained arrhythmia, is both cause and consequence of atrial remodeling, with atrial fibrosis playing a key role in AF maintenance, progression, and treatment response. Sex-specific differences in atrial fibrogenesis have been observed: young females exhibit lower extracellular matrix (ECM) protein levels than males, but these increase in aging females, likely due to estrogen (E2) loss during menopause. Testosterone (TS) reduces collagen production in fibroblasts (Fbs), the primary cellular drivers of fibrosis. However, the mechanistic basis for these sex hormone-dependent anti-fibrotic effects remains unclear. To identify and quantitatively investigate these mechanisms, we extended our computational model of atrial Fb signaling by incorporating E2 and TS pathways, and validated predictions against a broad set of experimental data distinct from those used to develop the model. Our model demonstrated high predictive accuracy with 81% concordance in cardiac Fbs and 100% in atrial Fbs under AF-relevant profibrotic stimuli, angiotensin II (AngII), and transforming growth factor β (TGFβ). Simulations revealed that both E2 and TS significantly attenuate profibrotic remodeling triggered by AngII and TGFβ. E2 exerted broad protection by suppressing Smad3 activation and upstream regulators of Ca 2+ signaling, reactive oxygen species, and JUN N-terminal kinase (JNK). TS showed limited protection against TGFβ-induced fibrogenesis but significantly blunted AngII-induced fibrotic responses by targeting Ca 2+ signaling through inhibition of IP3-mediated Ca 2+ entry and Smad3. This analysis identifies distinct, hormone-specific regulatory nodes through which E2 and TS mitigate fibrogenesis, offering mechanistic insight into observed sex differences in AF-associated fibrosis. Future work will incorporate progesterone to elucidate its individual and combined role alongside E2 and TS in modulating atrial fibrosis. These results establish a quantitative framework for exploring sex hormone regulation of atrial remodeling and highlight potential therapeutic targets for anti-fibrotic strategies.