Dual inhibition of TGFβ and PDGF improves RV remodeling and function in response to RV pressure or volume‐loading

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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Main Authors: 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
Format: Article
Language:English
Published: Wiley 2025-05-01
Series:Physiological Reports
Subjects:
congenital heart disease
fibrosis
hypertrophy
PDGF
pressure‐loading
right ventricle
Online Access:https://doi.org/10.14814/phy2.70339
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Summary: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.
ISSN:2051-817X

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