Computational modeling identifies protective mechanisms of estrogen and testosterone against atrial fibrosis
Abstract
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. AF prevalence rises with age, as sex hormone (estrogen, E2, and testosterone, TS) levels decline in both sexes, and aging-associated extracellular matrix (ECM) remodeling parallels these hormonal transitions during menopause and andropause. Furthermore, extensive experimental evidence supports the protective effect of E2 and TS against fibrotic remodeling. However, the mechanistic basis of sex hormone-dependent antifibrotic effects remains unclear. To identify potential underlying mechanisms, we extended our computational model of atrial-enriched fibroblast (Fb) by incorporating E2 and TS pathways. We validated predictions against a broad set of independent experimental data, demonstrating 81% concordance in cardiac Fbs and 100% in atrial Fbs under two AF-relevant profibrotic stimuli: angiotensin-II (AngII) and transforming growth factor-β (TGFβ). E2 and TS significantly attenuated profibrotic remodeling triggered by both AngII and TGFβ. E2 exerted protection by suppressing Smad3 and upstream regulators of Ca2+ signaling, reactive oxygen species (ROS) formation, and Jun N-terminal kinase (JNK). TS showed limited protection against TGFβ-induced fibrogenesis, but significantly blunted AngII-induced fibrotic responses mainly through Smad3. These analyses identified…
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