Dauz John D, Yazaki Kana, Akazawa Yohei, Meister Theo A, Kabir Golam, Kadowaki Sachiko, Honjo Osami, Heximer Scott P, Wald Rachel M, Connelly Kim A, Friedberg Mark K
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Division of Cardiology, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Physiol Rep. 2025 May;13(9):e70339. doi: 10.14814/phy2.70339.
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.
右心室（RV）压力和容量负荷会导致法洛四联症修复术后出现右心室纤维化，并伴有右心室功能障碍、发病率和死亡率。转化生长因子-β1（TGFβ1）和血小板衍生生长因子（PDGF）通过TGFβ经典和非经典信号通路激活共同的下游信号通路，从而促进其他器官中纤维母细胞的激活、增殖和纤维化。然而，PDGF以及TGFβ经典和非经典信号在右心室纤维化中的作用尚未完全明确。在此，我们研究使用曲尼司特（TRN）对TGFβ和PDGF进行双重抑制是否能改善因肺动脉环扎术（PAB）或肺动脉反流（PR）引起的右心室重塑。TRN降低了PAB大鼠的TGFβ经典信号，同时右心室纤维化、肥厚及右心室功能得到改善。对于PR，TRN降低了PDGFRβ表达并使ERK1/2活性恢复正常，这与右心室肥厚减轻和舒张期松弛改善相关。我们发现PDGF通过SMAD2/3、JNK和β-连环蛋白信号通路驱动右心室纤维母细胞的增殖和激活。我们的研究表明，TGFβ和PDGF是右心室纤维化的相互关联驱动因素，因此是改善右心室压力和容量负荷时右心室重塑的协同靶点。
