{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:16:44Z","timestamp":1753892204006,"version":"3.41.2"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T35OD010946"],"award-info":[{"award-number":["T35OD010946"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Fibrosis is a pathological process with few therapeutic options. Experimental molecules are being developed to counteract the fibrotic effects through TGF\u03b2 receptor inhibition. Additionally, phosphodiesterase 5 (PDE5) inhibitors also have anti-fibrotic effects; however, the mechanism of action remains unresolved. IPW5371 is an example of an experimental TGF\u03b2-mediated anti-fibrotic compound, and tadalafil is an example of a PDE5 inhibitor. Irradiation increases the frequency of fibrotic lesions, driven by the activation of the TGF\u03b2 pathway. We hypothesized that the TGF\u03b2 receptor and PDE5 inhibitor agents would be additive in their ability to prevent fibrosis development in tissues in a sub-lethal whole-body irradiation mouse model. However, the combined use of anti-fibrotic agents, tadalafil and IPW5371, caused increased male mouse mortality associated with ascending and thoracic aortic rupture compared to mice that only received one of the drugs. Following histopathological analysis of the mouse hearts, we also observed that irradiation protected against lesions caused by the combination therapy as non-irradiated male mice had significantly worse outcomes as compared to irradiated male mice, substantiating the drug\u2013drug interaction independent of the radiation effects. This important drug interaction needs further investigation as these agents are developed for anti-fibrosis therapy, and PDE5 inhibitors are commonly prescribed to male patients.<\/jats:p>","DOI":"10.3389\/fphar.2025.1537494","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T06:39:20Z","timestamp":1743575960000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Male mice treated with combined anti-fibrotic therapeutics, IPW5371 and tadalafil, are predisposed to adverse cardiovascular events"],"prefix":"10.3389","volume":"16","author":[{"given":"Jazz Q.","family":"Stephens","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uriel","family":"Blas-Machado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chrissy","family":"Sherrill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Caudell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Kock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley M.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordyn M.","family":"Whitfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barry","family":"Hart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kylie","family":"Kavanagh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"94","DOI":"10.5152\/npa.2016.12665","article-title":"Anterior cerebral artery dissection due to sildenafil use","volume":"54","author":"Anadol Kelleci","year":"2017","journal-title":"Noro Psikiyatr. Ars"},{"key":"B2","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1177\/0192623311416259","article-title":"Induction of heart valve lesions by small-molecule ALK5 inhibitors","volume":"39","author":"Anderton","year":"2011","journal-title":"Toxicol. Pathol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.canlet.2011.12.012","article-title":"Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury","volume":"327","author":"Azzam","year":"2012","journal-title":"Cancer Lett."},{"key":"B4","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1016\/j.ijrobp.2019.11.034","article-title":"Whole body irradiation induces diabetes and adipose insulin resistance in non-human primates","volume":"106","author":"Bacarella","year":"2019","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1S","DOI":"10.1293\/tox.29.3S-1","article-title":"Non-proliferative and proliferative lesions of the cardiovascular system of the rat and mouse","volume":"29","author":"Berridge","year":"2016","journal-title":"J. Toxicol. Pathol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"G483","DOI":"10.1152\/ajpgi.00079.2013","article-title":"Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment","volume":"305","author":"Clapper","year":"2013","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.devcel.2018.10.019","article-title":"Pericyte ALK5\/TIMP3 Axis contributes to endothelial morphogenesis in the developing brain","volume":"47","author":"Dave","year":"","journal-title":"Dev. Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.devcel.2018.01.018","article-title":"Pericyte ALK5\/TIMP3 Axis contributes to endothelial morphogenesis in the developing brain","volume":"44","author":"Dave","year":"","journal-title":"Dev. Cell"},{"key":"B9","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1667\/RR14357.1","article-title":"Late effects of total-body gamma irradiation on cardiac structure and function in male rhesus macaques","volume":"186","author":"DeBo","year":"2016","journal-title":"Radiat. Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.jocn.2012.04.023","article-title":"Vertebral artery dissection associated with sildenafil abuse","volume":"20","author":"Dersch","year":"2013","journal-title":"J. Clin. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/S1470-2045(12)70323-6","article-title":"Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study","volume":"13","author":"de Vathaire","year":"2012","journal-title":"Lancet Oncol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"R290","DOI":"10.1152\/ajpregu.00108.2017","article-title":"Changes in microvascular density differentiate metabolic health outcomes in monkeys with prior radiation exposure and subsequent skeletal muscle ECM remodeling","volume":"313","author":"Fanning","year":"2017","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1080\/09553002.2023.2173825","article-title":"IPW-5371 mitigates the delayed effects of acute radiation exposure in WAG\/RijCmcr rats when started 15 days after PBI with bone marrow sparing","volume":"99","author":"Fish","year":"2023","journal-title":"Int. J. Radiat. Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1007\/s00280-015-2895-4","article-title":"Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors","volume":"76","author":"Fujiwara","year":"2015","journal-title":"Cancer Chemother. Pharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1007\/s11684-014-0378-3","article-title":"Chronic inhibition of cyclic guanosine monophosphate-specific phosphodiesterase 5 prevented cardiac fibrosis through inhibition of transforming growth factor \u03b2-induced Smad signaling","volume":"8","author":"Gong","year":"2014","journal-title":"Front. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1016\/j.ejca.2014.01.014","article-title":"Adult life after childhood cancer in scandinavia: diabetes mellitus following treatment for cancer in childhood","volume":"50","author":"Holmqvist","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2647","DOI":"10.1161\/ATVBAHA.115.306573","article-title":"Postnatal deletion of the type II transforming growth factor-\u03b2 receptor in smooth muscle cells causes severe aortopathy in mice","volume":"35","author":"Hu","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"735","DOI":"10.3109\/09553002.2012.715793","article-title":"The effect of genetic background and dose on non-targeted effects of radiation","volume":"88","author":"Irons","year":"2012","journal-title":"Int. J. Radiat. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"S29","DOI":"10.1016\/0168-8227(94)90224-0","article-title":"Trends in the prevalence of diabetes mellitus among Hiroshima atomic bomb survivors","volume":"24","author":"Ito","year":"1994","journal-title":"Diabetes Res. Clin. Pract."},{"key":"B20","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1021\/acs.jcim.7b00568","article-title":"ADVERPred-web service for prediction of adverse effects of drugs","volume":"58","author":"Ivanov","year":"2018","journal-title":"J. Chem. Inf. Model"},{"key":"B21","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1111\/micc.12103","article-title":"The dynamic changes of capillary permeability and upregulation of VEGF in rats following radiation-induced brain injury","volume":"21","author":"Jin","year":"2014","journal-title":"Microcirculation"},{"key":"B22","doi-asserted-by":"publisher","first-page":"416","DOI":"10.2337\/db10-1116","article-title":"Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice","volume":"60","author":"Kang","year":"2011","journal-title":"Diabetes"},{"key":"B23","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1667\/RR13916.1","article-title":"Type 2 diabetes is a delayed late effect of whole-body irradiation in nonhuman primates","volume":"183","author":"Kavanagh","year":"2015","journal-title":"Radiat. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.athoracsur.2011.07.016","article-title":"Type B aortic dissection after the use of tadalafil","volume":"93","author":"Lameijer","year":"2012","journal-title":"Ann. Thorac. Surg."},{"key":"B25","doi-asserted-by":"publisher","first-page":"12014","DOI":"10.1074\/jbc.M114.615377","article-title":"Tadalafil integrates nitric oxide-hydrogen sulfide signaling to inhibit high glucose-induced matrix protein synthesis in podocytes","volume":"290","author":"Lee","year":"2015","journal-title":"J. Biol. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"155969","DOI":"10.1016\/j.cyto.2022.155969","article-title":"Platelet TGF-\u03b21 inhibits the migration and proliferation of smooth muscle cells in aneurysms","volume":"158","author":"Liu","year":"2022","journal-title":"Cytokine"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Lopez-Otin","year":"2013","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s13293-017-0141-y","article-title":"Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8","volume":"8","author":"Marek","year":"2017","journal-title":"Biol. Sex. Differ."},{"key":"B29","doi-asserted-by":"publisher","first-page":"162ra155","DOI":"10.1126\/scitranslmed.3004327","article-title":"Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy","volume":"4","author":"Martin","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e0119661","DOI":"10.1371\/journal.pone.0119661","article-title":"Low-dose irradiation affects expression of inflammatory markers in the heart of ApoE -\/- mice","volume":"10","author":"Mathias","year":"2015","journal-title":"PLoS One"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1001\/archinternmed.2009.209","article-title":"Diabetes mellitus in long-term survivors of childhood cancer. Increased risk associated with radiation therapy: a report for the childhood cancer survivor study","volume":"169","author":"Meacham","year":"2009","journal-title":"Arch. Intern Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1016\/j.ajpath.2020.01.004","article-title":"Fibroblast activation protein regulates lesion burden and the fibroinflammatory response in apoe-deficient mice in a sexually dimorphic manner","volume":"190","author":"Monslow","year":"2020","journal-title":"Am. J. Pathol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"5307","DOI":"10.1096\/fj.201700249R","article-title":"Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy","volume":"31","author":"Nio","year":"2017","journal-title":"FASEB J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"H1867","DOI":"10.1152\/ajpheart.00653.2015","article-title":"Effect of PDE5 inhibition on the modulation of sympathetic \u03b1-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans","volume":"309","author":"Nyberg","year":"","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e12508","DOI":"10.14814\/phy2.12508","article-title":"Potentiation of cGMP signaling increases oxygen delivery and oxidative metabolism in contracting skeletal muscle of older but not young humans","volume":"3","author":"Nyberg","year":"","journal-title":"Physiol. Rep."},{"key":"B36","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1161\/ATVBAHA.119.313863","article-title":"Interleukin-1 beta-mediated sex differences in kawasaki disease vasculitis development and response to treatment","volume":"40","author":"Porritt","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1667\/RR14403.2","article-title":"IPW-5371 proves effective as a radiation countermeasure by mitigating radiation-induced late effects","volume":"186","author":"Rabender","year":"2016","journal-title":"Radiat. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-1-4939-7113-8_1","article-title":"Human fibrotic diseases: current challenges in fibrosis research","volume":"1627","author":"Rosenbloom","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e0153694","DOI":"10.1371\/journal.pone.0153694","article-title":"The effect of sorafenib, tadalafil and macitentan treatments on thyroxin-induced hemodynamic changes and cardiac abnormalities","volume":"11","author":"Saad","year":"2016","journal-title":"PLoS One"},{"key":"B40","doi-asserted-by":"publisher","first-page":"6976","DOI":"10.1158\/1078-0432.CCR-19-1338","article-title":"Phase II study of the ALK5 inhibitor galunisertib in very low-low-and intermediate-risk myelodysplastic syndromes","volume":"25","author":"Santini","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.ijrobp.2006.08.071","article-title":"Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data?","volume":"67","author":"Schultz-Hector","year":"2007","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"B42","doi-asserted-by":"publisher","first-page":"506348","DOI":"10.1155\/2014\/506348","article-title":"Mouse bone marrow-derived endothelial progenitor cells do not restore radiation-induced microvascular damage","volume":"2014","author":"Seemann","year":"2014","journal-title":"ISRN Cardiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"eaaw8283","DOI":"10.1126\/scitranslmed.aaw8283","article-title":"Blood-brain barrier dysfunction in aging induces hyperactivation of TGF\u03b2 signaling and chronic yet reversible neural dysfunction","volume":"11","author":"Senatorov","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1080\/13543784.2020.1757648","article-title":"BIO 300: a promising radiation countermeasure under advanced development for acute radiation syndrome and the delayed effects of acute radiation exposure","volume":"29","author":"Singh","year":"2020","journal-title":"Expert Opin. Investig. Drugs"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1667\/RADE-23-00202.1","article-title":"A novel TGF\u03b2 receptor inhibitor, IPW-5371, prevents diet-induced hepatic steatosis and insulin resistance in irradiated mice","volume":"202","author":"Szalanczy","year":"2024","journal-title":"Radiat. Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00395-004-0504-5","article-title":"Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells","volume":"100","author":"Tantini","year":"2005","journal-title":"Basic Res. Cardiol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1124\/jpet.105.092544","article-title":"Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta","volume":"316","author":"Teixeira","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B48","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.ijrobp.2021.03.058","article-title":"Clinicopathologic and transcriptomic analysis of radiation-induced lung injury in nonhuman primates","volume":"111","author":"Thakur","year":"2021","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"B49","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1097\/HP.0000000000000357","article-title":"Delayed effects of acute radiation exposure in a murine model of the H-ars: multiple-organ injury consequent to <10 Gy total body irradiation","volume":"109","author":"Unthank","year":"2015","journal-title":"Health Phys."},{"key":"B50","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1200\/JCO.2015.63.4444","article-title":"Radiation dose-response relationship for risk of coronary heart disease in survivors of hodgkin lymphoma","volume":"34","author":"van Nimwegen","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"11396","DOI":"10.1096\/fj.201900601RR","article-title":"Cyclophilin A contributes to aortopathy induced by postnatal loss of smooth muscle TGFBR1","volume":"33","author":"Zhou","year":"2019","journal-title":"FASEB J."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10735-021-10035-9","article-title":"RUNX3 is up-regulated in abdominal aortic aneurysm and regulates the function of vascular smooth muscle cells by regulating TGF-\u03b21","volume":"53","author":"Zhou","year":"2022","journal-title":"J. Mol. Histol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1537494\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T06:39:21Z","timestamp":1743575961000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1537494\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,2]]},"references-count":52,"alternative-id":["10.3389\/fphar.2025.1537494"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1537494","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2025,4,2]]},"article-number":"1537494"}}