{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T22:35:36Z","timestamp":1783463736238,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012895","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000}}],"reference-count":90,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012895","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T18:43:01Z","timestamp":1765392181000},"page":"e1012895","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Modeling the interplay of sex hormones in cardiac hypertrophic signaling"],"prefix":"10.1371","volume":"21","author":[{"given":"Adhithi","family":"Lakshmikanthan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minnie","family":"Kay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0069-4538","authenticated-orcid":true,"given":"Pim J.A.","family":"Oomen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"issue":"8","key":"pcbi.1012895.ref001","doi-asserted-by":"crossref","DOI":"10.1161\/CIR.0000000000001209","article-title":"2024 Heart disease and stroke statistics: A report of US and global data from the American Heart Association","volume":"149","author":"SS Martin","year":"2024","journal-title":"Circulation."},{"issue":"1","key":"pcbi.1012895.ref002","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13293-019-0223-0","article-title":"Sex-specific influence on cardiac structural remodeling and therapy in cardiovascular disease","volume":"10","author":"EL Kessler","year":"2019","journal-title":"Biol Sex Differ."},{"key":"pcbi.1012895.ref003","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3389\/fgene.2016.00183","article-title":"Large scale gene expression meta-analysis reveals tissue-specific, sex-biased gene expression in humans","volume":"7","author":"BT Mayne","year":"2016","journal-title":"Front Genet."},{"issue":"21","key":"pcbi.1012895.ref004","article-title":"Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation","volume":"56","author":"W Shi","year":"2021","journal-title":"Dev Cell."},{"key":"pcbi.1012895.ref005","doi-asserted-by":"crossref","first-page":"110972","DOI":"10.1016\/j.mce.2020.110972","article-title":"The endocrinological component and signaling pathways associated to cardiac hypertrophy","volume":"518","author":"APC Takano","year":"2020","journal-title":"Mol Cell Endocrinol."},{"issue":"1","key":"pcbi.1012895.ref006","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s12265-019-09907-z","article-title":"Gender differences in cardiac hypertrophy","volume":"13","author":"J Wu","year":"2020","journal-title":"J Cardiovasc Transl Res."},{"issue":"5","key":"pcbi.1012895.ref007","article-title":"Estimation of local myocardial stress","volume":"242","author":"RF Janz","year":"1982","journal-title":"Am J Physiol."},{"key":"pcbi.1012895.ref008","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1161\/01.HYP.26.6.979","article-title":"Gender differences in left ventricular growth","volume":"26","author":"G de Simone","year":"1995","journal-title":"Hypertension."},{"issue":"1","key":"pcbi.1012895.ref009","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12968-020-00692-2","article-title":"Cardiovascular magnetic resonance normal values in children for biventricular wall thickness and mass","volume":"23","author":"S Krupickova","year":"2021","journal-title":"J Cardiovasc Magn Reson."},{"issue":"7","key":"pcbi.1012895.ref010","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1016\/j.cell.2015.05.026","article-title":"Dynamics of cell generation and turnover in the human heart","volume":"161","author":"O Bergmann","year":"2015","journal-title":"Cell."},{"issue":"17","key":"pcbi.1012895.ref011","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1016\/j.jacc.2010.01.022","article-title":"Long-term reverse remodeling with cardiac resynchronization therapy: Results of extended echocardiographic follow-up","volume":"55","author":"D Verhaert","year":"2010","journal-title":"J Am Coll Cardiol."},{"key":"pcbi.1012895.ref012","doi-asserted-by":"crossref","unstructured":"Dorak MT. 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