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

Area of Science:

• Cardiovascular Research
• Fibrosis Mechanisms
• Molecular Signaling

Background:

• Right ventricular (RV) pressure and volume overload lead to RV fibrosis, dysfunction, and mortality, particularly in repaired Tetralogy of Fallot.
• Transforming-growth factor-β1 (TGFβ1) and platelet-derived growth factor (PDGF) signaling pathways are implicated in fibrosis in other organs, but their role in RV fibrosis is not fully understood.

Purpose of the Study:

• To investigate the role of PDGF and TGFβ signaling in RV fibrosis.
• To determine if dual inhibition of TGFβ and PDGF using Tranilast (TRN) can improve RV remodeling in response to pulmonary artery banding (PAB) or pulmonary regurgitation (PR).

Main Methods:

• Utilized rat models of PAB and PR to induce RV pressure and volume overload.
• Administered Tranilast (TRN) to assess its effects on RV fibrosis, hypertrophy, and function.
• Analyzed TGFβ canonical signaling, PDGFRβ expression, ERK1/2 activity, and downstream signaling pathways (SMAD2/3, JNK, β-catenin).

Main Results:

• TRN reduced TGFβ canonical signaling in PAB rats, improving RV fibrosis, hypertrophy, and function.
• In PR models, TRN decreased PDGFRβ expression and normalized ERK1/2 activity, leading to reduced RV hypertrophy and improved diastolic relaxation.
• Identified PDGF as a driver of RV fibroblast proliferation and activation through SMAD2/3, JNK, and β-catenin signaling.

Conclusions:

• TGFβ and PDGF signaling pathways are interconnected and contribute significantly to RV fibrosis.
• Dual inhibition of TGFβ and PDGF presents a promising synergistic therapeutic strategy for improving RV remodeling in conditions of pressure and volume loading.