Academic Journal
Computational modeling identifies protective mechanisms of estrogen and testosterone against atrial fibrosis.
| Τίτλος: | Computational modeling identifies protective mechanisms of estrogen and testosterone against atrial fibrosis. |
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| Συγγραφείς: | Khorasani N; Department of Pharmacology, University of California, Davis, California, United States., Morotti S; Department of Pharmacology, University of California, Davis, California, United States., Saucerman JJ; Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States., Dobrev D; Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.; Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada.; Department of Integrative Physiology, Baylor College of Medicine, Houston, Texas, United States., Grandi E; Department of Pharmacology, University of California, Davis, California, United States. |
| Πηγή: | American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2026 Aug 01; Vol. 331 (2), pp. H407-H422. Date of Electronic Publication: 2026 Jun 16. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901228 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1539 (Electronic) Linking ISSN: 03636135 NLM ISO Abbreviation: Am J Physiol Heart Circ Physiol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Bethesda, Md. : American Physiological Society |
| Ιατρικοί όροι (MeSH): | Heart Atria*/pathology , Heart Atria*/metabolism , Heart Atria*/drug effects , Testosterone*/pharmacology , Fibroblasts*/metabolism , Fibroblasts*/drug effects , Fibroblasts*/pathology , Estrogens*/pharmacology , Atrial Remodeling*/drug effects , Atrial Fibrillation*/metabolism , Atrial Fibrillation*/pathology , Atrial Fibrillation*/prevention & control , Estradiol*/pharmacology , Computer Simulation* , Models, Cardiovascular*, Smad3 Protein/metabolism ; Transforming Growth Factor beta/pharmacology ; Angiotensin II/pharmacology ; Calcium Signaling/drug effects ; Reactive Oxygen Species/metabolism ; Fibrosis ; Humans ; Animals ; Signal Transduction |
| Περίληψη: | 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 hormone-specific regulatory nodes through which E2 and TS mitigate atrial fibrogenesis, offering mechanistic insight into how loss of sex hormone-mediated protection may contribute to age- and sex-dependent atrial remodeling. Our findings provide a quantitative framework for exploring sex hormone-mediated regulation of atrial remodeling and highlight potential therapeutic targets for antifibrotic AF treatment.NEW & NOTEWORTHY We developed a sex-informed computational model of atrial Fb signaling and used it to identify the mechanistic basis of sex hormone-dependent antifibrotic effects. TS acted primarily through Smad3, whereas ROS-JNK signaling emerged as a dominant mediator of E2-dependent antifibrotic protection, largely through coordinated feedback regulation. These findings offer hormone-specific regulatory nodes that may serve as a potential target for durable antifibrotic therapy in AF across sex and age. |
| Grant Information: | R03AG086695 HHS | NIH | National Institute on Aging (NIA); R01 HL165704 United States HL NHLBI NIH HHS; R01HL136389 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R01HL176651 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R01 HL131517 United States HL NHLBI NIH HHS; R01 HL162925 United States HL NHLBI NIH HHS; R01HL171586 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); Research Training Group 2989 (project 517043330) Deutsche Forschungsgemeinschaft (DFG); R01HL162925 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R00 HL138160 United States HL NHLBI NIH HHS; R01HL131517 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R01HL170521 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R01HL171057 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); P01 HL141084 United States HL NHLBI NIH HHS; R01HL141214 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R01 HL176651 United States HL NHLBI NIH HHS; R01 HL171057 United States HL NHLBI NIH HHS; R01 HL171586 United States HL NHLBI NIH HHS; R01 HL136389 United States HL NHLBI NIH HHS; R01 HL170521 United States HL NHLBI NIH HHS; 25POST1356871 American Heart Association (AHA); P01HL141084 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R00HL138160 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R01HL165704 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R03 AG086695 United States AG NIA NIH HHS; R01HL16483 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R01 HL164838 United States HL NHLBI NIH HHS; 965286 European Union large-scale network grant; R01HL172417 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); R01 HL141214 United States HL NHLBI NIH HHS |
| Contributed Indexing: | Keywords: atrial fibrillation; atrial fibrosis; computational modeling; estrogen; testosterone |
| Substance Nomenclature: | 3XMK78S47O (Testosterone) 0 (Estrogens) 0 (Smad3 Protein) 0 (Transforming Growth Factor beta) 11128-99-7 (Angiotensin II) 0 (Reactive Oxygen Species) 4TI98Z838E (Estradiol) |
| Entry Date(s): | Date Created: 20260616 Date Completed: 20260707 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| PubMed Central ID: | PMC13348827 |
| DOI: | 10.1152/ajpheart.00249.2026 |
| PMID: | 42302746 |
| Βάση Δεδομένων: | MEDLINE |
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