Dual inhibition of TGFβ and PDGF improves RV remodeling and function in response to RV pressure or volume‐loading
Abstract Right ventricular (RV) pressure and volume loading induce RV fibrosis in association with RV dysfunction, morbidity, and mortality in repaired tetralogy of Fallot. Transforming‐growth factor‐β1 (TGFβ1) and platelet‐derived growth factor (PDGF) activate common downstream signaling pathways v...
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| Format: | Article |
| Language: | English |
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Wiley
2025-05-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.70339 |
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| author | John D. Dauz Kana Yazaki Yohei Akazawa Theo A. Meister Golam Kabir Sachiko Kadowaki Osami Honjo Scott P. Heximer Rachel M. Wald Kim A. Connelly Mark K. Friedberg |
| author_facet | John D. Dauz Kana Yazaki Yohei Akazawa Theo A. Meister Golam Kabir Sachiko Kadowaki Osami Honjo Scott P. Heximer Rachel M. Wald Kim A. Connelly Mark K. Friedberg |
| author_sort | John D. Dauz |
| collection | DOAJ |
| description | Abstract Right ventricular (RV) pressure and volume loading induce RV fibrosis in association with RV dysfunction, morbidity, and mortality in repaired tetralogy of Fallot. Transforming‐growth factor‐β1 (TGFβ1) and platelet‐derived growth factor (PDGF) activate common downstream signaling pathways via TGFβ canonical and non‐canonical signaling to promote increased fibroblast activation, proliferation, and fibrosis in other organs. However, the role of PDGF and TGFβ canonical and non‐canonical signaling in RV fibrosis is incompletely characterized. Here, we investigate whether dual inhibition of TGFβ and PDGF, using Tranilast (TRN), improves RV remodeling in response to pulmonary artery banding (PAB) or pulmonary regurgitation (PR). TRN reduced TGFβ canonical signaling in PAB rats associated with improved RV fibrosis, hypertrophy, and RV function. In response to PR, TRN reduced PDGFRβ 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 β‐catenin signaling. Our studies suggest that TGFβ and PDGF are interconnected drivers of RV fibrosis and hence synergistic targets to improve RV remodeling in RV pressure and volume loading. |
| format | Article |
| id | doaj-art-bab26a7d19e247838dec81e2da1096d9 |
| institution | Kabale University |
| issn | 2051-817X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj-art-bab26a7d19e247838dec81e2da1096d92025-08-20T03:49:44ZengWileyPhysiological Reports2051-817X2025-05-01139n/an/a10.14814/phy2.70339Dual inhibition of TGFβ and PDGF improves RV remodeling and function in response to RV pressure or volume‐loadingJohn D. Dauz0Kana Yazaki1Yohei Akazawa2Theo A. Meister3Golam Kabir4Sachiko Kadowaki5Osami Honjo6Scott P. Heximer7Rachel M. Wald8Kim A. Connelly9Mark K. Friedberg10Institute of Medical Science University of Toronto Toronto Ontario CanadaDivision of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children Toronto Ontario CanadaDivision of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children Toronto Ontario CanadaDivision of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children Toronto Ontario CanadaLi Ka Shing Knowledge Institute Keenan Research Centre, St. Michael's Hospital Toronto Ontario CanadaDivision of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children Toronto Ontario CanadaDivision of Cardiovascular Surgery The Labatt Family Heart Centre, The Hospital for Sick Children Toronto Ontario CanadaDepartment of Physiology University of Toronto Toronto Ontario CanadaDivision of Cardiology, Labatt Family Heart Centre The Hospital for Sick Children Toronto Ontario CanadaInstitute of Medical Science University of Toronto Toronto Ontario CanadaInstitute of Medical Science University of Toronto Toronto Ontario CanadaAbstract Right ventricular (RV) pressure and volume loading induce RV fibrosis in association with RV dysfunction, morbidity, and mortality in repaired tetralogy of Fallot. Transforming‐growth factor‐β1 (TGFβ1) and platelet‐derived growth factor (PDGF) activate common downstream signaling pathways via TGFβ canonical and non‐canonical signaling to promote increased fibroblast activation, proliferation, and fibrosis in other organs. However, the role of PDGF and TGFβ canonical and non‐canonical signaling in RV fibrosis is incompletely characterized. Here, we investigate whether dual inhibition of TGFβ and PDGF, using Tranilast (TRN), improves RV remodeling in response to pulmonary artery banding (PAB) or pulmonary regurgitation (PR). TRN reduced TGFβ canonical signaling in PAB rats associated with improved RV fibrosis, hypertrophy, and RV function. In response to PR, TRN reduced PDGFRβ 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 β‐catenin signaling. Our studies suggest that TGFβ and PDGF are interconnected drivers of RV fibrosis and hence synergistic targets to improve RV remodeling in RV pressure and volume loading.https://doi.org/10.14814/phy2.70339congenital heart diseasefibrosishypertrophyPDGFpressure‐loadingright ventricle |
| spellingShingle | John D. Dauz Kana Yazaki Yohei Akazawa Theo A. Meister Golam Kabir Sachiko Kadowaki Osami Honjo Scott P. Heximer Rachel M. Wald Kim A. Connelly Mark K. Friedberg Dual inhibition of TGFβ and PDGF improves RV remodeling and function in response to RV pressure or volume‐loading Physiological Reports congenital heart disease fibrosis hypertrophy PDGF pressure‐loading right ventricle |
| title | Dual inhibition of TGFβ and PDGF improves RV remodeling and function in response to RV pressure or volume‐loading |
| title_full | Dual inhibition of TGFβ and PDGF improves RV remodeling and function in response to RV pressure or volume‐loading |
| title_fullStr | Dual inhibition of TGFβ and PDGF improves RV remodeling and function in response to RV pressure or volume‐loading |
| title_full_unstemmed | Dual inhibition of TGFβ and PDGF improves RV remodeling and function in response to RV pressure or volume‐loading |
| title_short | Dual inhibition of TGFβ and PDGF improves RV remodeling and function in response to RV pressure or volume‐loading |
| title_sort | dual inhibition of tgfβ and pdgf improves rv remodeling and function in response to rv pressure or volume loading |
| topic | congenital heart disease fibrosis hypertrophy PDGF pressure‐loading right ventricle |
| url | https://doi.org/10.14814/phy2.70339 |
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