{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:24:39Z","timestamp":1783013079951,"version":"3.54.6"},"reference-count":59,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT\u201016249"],"award-info":[{"award-number":["PJT\u201016249"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Right ventricular (RV) pressure and volume loading induce RV fibrosis in association with RV dysfunction, morbidity, and mortality in repaired tetralogy of Fallot. Transforming\u2010growth factor\u2010\u03b21 (TGF\u03b21) and platelet\u2010derived growth factor (PDGF) activate common downstream signaling pathways via TGF\u03b2 canonical and non\u2010canonical signaling to promote increased fibroblast activation, proliferation, and fibrosis in other organs. However, the role of PDGF and TGF\u03b2 canonical and non\u2010canonical signaling in RV fibrosis is incompletely characterized. Here, we investigate whether dual inhibition of TGF\u03b2 and PDGF, using Tranilast (TRN), improves RV remodeling in response to pulmonary artery banding (PAB) or pulmonary regurgitation (PR). TRN reduced TGF\u03b2 canonical signaling in PAB rats associated with improved RV fibrosis, hypertrophy, and RV function. In response to PR, TRN reduced PDGFR\u03b2 expression and normalized ERK1\/2 activity, which were associated with reduced RV hypertrophy and improved diastolic relaxation. We identify that PDGF drives RV fibroblast proliferation and activation via SMAD2\/3, JNK, and \u03b2\u2010catenin signaling. Our studies suggest that TGF\u03b2 and PDGF are interconnected drivers of RV fibrosis and hence synergistic targets to improve RV remodeling in RV pressure and volume loading.<\/jats:p>","DOI":"10.14814\/phy2.70339","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T09:51:57Z","timestamp":1746438717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dual inhibition of\n                    <scp>TGF\u03b2<\/scp>\n                    and\n                    <scp>PDGF<\/scp>\n                    improves\n                    <scp>RV<\/scp>\n                    remodeling and function in response to\n                    <scp>RV<\/scp>\n                    pressure or volume\u2010loading"],"prefix":"10.14814","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9879-0896","authenticated-orcid":false,"given":"John D.","family":"Dauz","sequence":"first","affiliation":[{"name":"Institute of Medical Science University of Toronto  Toronto Ontario Canada"},{"name":"Division of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kana","family":"Yazaki","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Akazawa","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo A.","family":"Meister","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Golam","family":"Kabir","sequence":"additional","affiliation":[{"name":"Li Ka Shing Knowledge Institute Keenan Research Centre, St. Michael's Hospital  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Kadowaki","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osami","family":"Honjo","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Surgery The Labatt Family Heart Centre, The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott P.","family":"Heximer","sequence":"additional","affiliation":[{"name":"Department of Physiology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel M.","family":"Wald","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Toronto Congenital Cardiac Centre for Adults Peter Munk Cardiac Centre  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim A.","family":"Connelly","sequence":"additional","affiliation":[{"name":"Institute of Medical Science University of Toronto  Toronto Ontario Canada"},{"name":"Li Ka Shing Knowledge Institute Keenan Research Centre, St. Michael's Hospital  Toronto Ontario Canada"},{"name":"Department of Physiology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4108-5560","authenticated-orcid":false,"given":"Mark K.","family":"Friedberg","sequence":"additional","affiliation":[{"name":"Institute of Medical Science University of Toronto  Toronto Ontario Canada"},{"name":"Division of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Department of Physiology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00467.2020"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.11.002"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60657-7"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2004.03.006"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2021.1982322"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/ehjci\/jez068"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201809-1737OC"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0205196"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.418"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.18388\/abp.2018_2635"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.echo.2020.12.011"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.52.37413"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611871200"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa324"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/ehjci\/jes067"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000138397.60956.c2"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP283165"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00343.2019"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.965204"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.557514"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0042513"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201708689"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M808490200"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.231514"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000139066.77892.04"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01167.2006"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI94753"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2016-0374OC"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0169564"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00423.2014"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-117804"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd11020054"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00444.2008"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00186.2005"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.026238"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00149"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2008.01.040"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.321725"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0146767"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175791"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.115.002636"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.001873"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00975.2017"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00776.2012"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00054.2009"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-09-0027"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.08.028"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hlc.2012.08.054"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.007928"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.132.4.741"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00609"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/chd.12762"},{"key":"e_1_2_11_54_1","first-page":"1","article-title":"Feedback activation of basic fibroblast growth factor signaling via the Wnt\/\u03b2\u2010catenin pathway in skin fibroblasts","volume":"8","author":"Wang X.","year":"2017","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvad129"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2018-313961"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00322.2024"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/24911"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00130.2013"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.06.023"}],"container-title":["Physiological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.70339","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.14814\/phy2.70339","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.70339","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:02:11Z","timestamp":1783011731000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.14814\/phy2.70339"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5]]},"references-count":59,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.14814\/phy2.70339"],"URL":"https:\/\/doi.org\/10.14814\/phy2.70339","archive":["Portico"],"relation":{},"ISSN":["2051-817X","2051-817X"],"issn-type":[{"value":"2051-817X","type":"print"},{"value":"2051-817X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5]]},"assertion":[{"value":"2024-10-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70339"}}